Compositions and methods for inhibition of the JAK pathway

ABSTRACT

The invention encompasses compounds having formula I and the compositions and methods using these compounds in the treatment of conditions in which modulation of the JAK pathway or inhibition of JAK kinases are therapeutically useful.

I. CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.11/875,772, filed on Oct. 19, 2007, now U.S. Pat. No. 8,193,197 whichclaims the benefit of the earlier filing date of U.S. provisionalApplication No. 60/862,162, filed Oct. 19, 2006. Each of these priorapplications is incorporated in its entirety herein by reference.

II. INTRODUCTION

a. Field

The present invention relates to compounds, prodrugs, and methods ofusing these compounds and prodrugs thereof in the treatment ofconditions in which modulation of the JAK pathway or inhibition of JAKkinases are therapeutically useful.

b. Background

Protein kinases constitute a large family of structurally relatedenzymes that are responsible for the control of a variety of signaltransduction processes within cells (see, e.g., Hardie and Hanks, TheProtein Kinase Facts Book, I and II, Academic Press, San Diego, Calif.,1995). Protein kinases are thought to have evolved from a commonancestral gene due to the conservation of their structure and catalyticfunction. Almost all kinases contain a similar 250-300 amino acidcatalytic domain. The kinases can be categorized into families by thesubstrates they phosphorylate (e.g., protein-tyrosine,protein-serine/threonine, lipids, etc.). Sequence motifs have beenidentified that generally correspond to each of these families (see,e.g., Hanks & Hunter, (1995), FASEB J. 9:576-596; Knighton et al.,(1991), Science 253:407-414; Hiles et al., (1992), Cell 70:419-429; Kunzet al., (1993), Cell 73:585-596; Garcia-Bustos et al., (1994), EMBO J.13:2352-2361).

JAK kinases (JAnus Kinases) are a family of cytoplasmic protein tyrosinekinases including JAK1, JAK2, JAK3 and TYK2. Each of the JAK kinases isselective for the receptors of certain cytokines, though multiple JAKkinases can be affected by particular cytokine or signaling pathways.Studies suggest that JAK3 associates with the common gamma (γc) chain ofthe various cytokine receptors. JAK3 in particular selectively binds toreceptors and is part of the cytokine signaling pathway for IL-2, IL-4,IL-7, IL-9, IL-15 and IL-21. JAK1 interacts with, among others, thereceptors for cytokines IL-2, IL-4, IL-7, IL-9 and IL-21, while JAK2interacts with, among others, the receptors for IL-9 and TNF-α. Upon thebinding of certain cytokines to their receptors (e.g., IL-2, IL-4, IL-7,IL-9, IL-15 and IL-21), receptor oligomerization occurs, resulting inthe cytoplasmic tails of associated JAK kinases being brought intoproximity and facilitating the trans-phosphorylation of tyrosineresidues on the JAK kinase. This trans-phosphorylation results in theactivation of the JAK kinase.

Phosphorylated JAK kinases bind various STAT (Signal Transducer andActivator of Transcription) proteins. STAT proteins, which are DNAbinding proteins activated by phosphorylation of tyrosine residues,function both as signaling molecules and transcription factors andultimately bind to specific DNA sequences present in the promoters ofcytokine-responsive genes (Leonard et al., (2000), J. Allergy Clin.Immunol. 105:877-888). JAK/STAT signaling has been implicated in themediation of many abnormal immune responses such as allergies, asthma,autoimmune diseases such as transplant (allograft) rejection, rheumatoidarthritis, amyotrophic lateral sclerosis and multiple sclerosis, as wellas in solid and hematologic malignancies such as leukemia and lymphomas.For a review of the pharmaceutical intervention of the JAK/STAT pathwaysee Frank, (1999), Mol. Med. 5:432:456 and Seidel et al., (2000),Oncogene 19:2645-2656.

As described above, JAKs are crucial components of diverse signaltransduction pathways that govern important cellular functions,including cell survival, proliferation, differentiation and apoptosis.Interfering with JAK activity may lead to the loss of a vital signaltransduction pathway, thereby disrupting normal cellular processesneeded for cell survival. Therefore, it is important to selectivelyinhibit particular JAKs that are involved in various disease states.

JAK2 associates with cytokine receptors and is essential for signaltransduction by mediating tyrosine phosphorylation. Kinase activity isregulated by a series of interactions beginning with the requirement tobind to specific domains in receptors, suppression of activation by thepseudokinase domain, and the requirement for phosphorylation within theactivation loop. Recent studies have implicated de-regulation of JAK2kinase activity by chromosomal translocations in hematopoietic tumorsand mutations within the pseudokinase domain in a spectrum ofmyeloproliferative diseases (Ihle, J N et al., Current Opinion inGenetics and Development (2007) 17:1, 8-14.

Also, JAK2 has been suggested to be involved in the upregulation ofangiotensinogen promoter activity in hypertrophy and ischemia (MascarenoE, et al. (2000) Mol. Cell. Biochem., 212:171-175; and Mascareno E, etal (2001) Circulation, 104:1). One particular tyrphostin, AG490,selectively inhibits JAK2 and has been proposed for treating cancer(Meydan N, et al. (1996) Nature, 379:645). Administration of tyrphostinAG490 has been suggested to afford cardioprotection to hearts subjectedto ischemia/reperfusion (Mascareno E, et al. (2000) Mol. Cell. Biochem.,212:171 and Mascareno E, et al (2001) Circulation, 104:1). TG101209, aJAK2-selective compound, has been recently shown to be effective ininhibiting mutations in myeloproliferative disorders (Pardanani A, etal. (2007) Leukemia, 1-11).

JAK3 in particular has been implicated in a variety of biologicalprocesses. For example, the proliferation and survival of murine mastcells induced by IL-4 and IL-9 have been shown to be dependent on JAK3-and gamma chain-signaling (Suzuki et al., (2000), Blood 96:2172-2180).JAK3 also plays a crucial role in IgE receptor-mediated mast celldegranulation responses (Malaviya et al., (1999), Biochem. Biophys. Res.Commun. 257:807-813), and inhibition of JAK3 kinase has been shown toprevent type I hypersensitivity reactions, including anaphylaxis(Malaviya et al., (1999), J. Biol. Chem. 274:27028-27038). JAK3inhibition has also been shown to result in immune suppression forallograft rejection (Kirken, (2001), Transpl. Proc. 33:3268-3270). JAK3kinases have also been implicated in the mechanism involved in early andlate stages of rheumatoid arthritis (Muller-Ladner et al., (2000), J.Immunol. 164:3894-3901); familial amyotrophic lateral sclerosis (Trieuet al., (2000), Biochem Biophys. Res. Commun. 267:22-25); leukemia(Sudbeck et al., (1999), Clin. Cancer Res. 5:1569-1582); mycosisfungoides, a form of T-cell lymphoma (Nielsen et al., (1997), Prac.Natl. Acad. Sci. USA 94:6764-6769); and abnormal cell growth (Yu et al.,(1997), J. Immunol. 159:5206-5210; Catlett-Falcone et al., (1999),Immunity 10:105-115).

The JAK kinases, including JAK3, are abundantly expressed in primaryleukemic cells from children with acute lymphoblastic leukemia, the mostcommon form of childhood cancer, and studies have correlated STATactivation in certain cells with signals regulating apoptosis (Demoulinet al., (1996), Mol. Cell. Biol. 16:4710-6; Jurlander et al., (1997),Blood. 89:4146-52; Kaneko et al., (1997), Clin. Exp. Immun. 109:185-193;and Nakamura et al., (1996), J. Biol. Chem. 271:19483-8). They are alsoknown to be important to lymphocyte differentiation, function andsurvival. JAK-3 in particular plays an essential role in the function oflymphocytes, macrophages, and mast cells. Given the importance of thisJAK kinase, compounds which modulate the JAK pathway, including thoseselective for JAK3, can be useful for treating diseases or conditionswhere the function of lymphocytes, macrophages, or mast cells isinvolved (Kudlacz et al., (2004) Am. J. Transplant 4:51-57; Changelian(2003) Science 302:875-878). Conditions in which targeting of the JAKpathway or modulation of the JAK kinases, particularly JAK3, arecontemplated to be therapeutically useful include, leukemia, lymphoma,transplant rejection (e.g., pancreas islet transplant rejection, bonemarrow transplant applications (e.g., graft-versus-host disease),autoimmune diseases (e.g., diabetes), and inflammation (e.g., asthma,allergic reactions). Conditions which can benefit for inhibition of JAK3are discussed in greater detail below.

In view of the numerous conditions that are contemplated to benefit bytreatment involving modulation of the JAK pathway it is immediatelyapparent that new compounds that modulate JAK pathways and methods ofusing these compounds should provide substantial therapeutic benefits toa wide variety of patients. Provided herein are novel2,4-pyrimidinediamine compounds for use in the treatment of conditionsin which targeting of the JAK pathway or inhibition of JAK kinases,particularly JAK3, can be therapeutically useful.

Patents and patent applications related to modulation of the JAK pathwayinclude: U.S. Pat. Nos. 5,728,536; 6,080,747; 6,080,748; 6,133,305;6,177,433; 6,210,654; 6,313,130; 6,316,635; 6,433,018; 6,486,185;6,506,763; 6,528,509; 6,593,357; 6,608,048; 6,610,688; 6,635,651;6,677,368; 6,683,082; 6,696,448; 6,699,865; 6,777,417; 6,784,195;6,825,190; 6,506,763; 6,784,195; 6,528,509; 6,608,048; 7,105,529;6,699,865; 6,825,190; 6,815,439; 6,949,580; 7,056,944; 6,998,391;7,074,793; 6,969,760; U.S. Pat. App. Pub. No. 2001/0007033 A1;2002/0115173 A1; 2002/0137141 A1; 2003/0236244 A1; 2004/0102455 A1;2004/0142404 A1; 2004/0147507 A1; and 2004/0214817 A1; and Internationalpatent applications WO 95/03701A1; WO 99/15500A1; WO 00/00202A1; WO00/10981A1; WO 00/47583A1; WO 00/51587A2; WO 00/55159A2; WO 01/42246A2;WO 01/45641A2; WO 01/52892A2; WO 01/56993A2; WO 01/57022A2; WO01/72758A1; WO 02/00661A1; WO 02/43735A1; WO 02/48336A2; WO 02/060492A1;WO 02/060927A1; WO 02/096909A1; WO 02/102800A1; WO 03/020698A2; WO03/048162A1; WO 03/101989A1; WO 2004/016597A2; WO 2004/041789A1; WO2004/041810A1; WO 2004/041814A1; WO 2004/046112A2; WO 2004/046120A2; WO2004/047843A1; WO 2004/058749A1; WO 2004/058753A1; WO 2004/085388A2; WO2004/092154A1; WO 2005/009957A1; WO 2005/016344A1; WO 2005/028475A2; andWO 2005/033107A1.

Patents and patent applications describing substituted pyrimidinediaminecompounds include: U.S. application Ser. No. 10/355,543 filed Jan. 31,2003 (US2004/0029902A1), international application Serial No.PCT/US03/03022 filed Jan. 31, 2003 (WO 03/063794), U.S. application Ser.No. 10/631,029 filed Jul. 29, 2003, international application Serial No.PCT/US03/24087 (WO 04/014382), U.S. application Ser. No. 10/903,263filed Jul. 30, 2004, and international application Serial No.PCT/US2004/24716 (WO 05/016893), the disclosures of which areincorporated herein by reference. Substituted pyrimidinediaminecompounds are also described in international patent applicationpublication numbers: WO 02/059110, WO 03/074515, WO 03/106416, WO03/066601, WO 03/063794, WO 04/046118, WO 05/016894, WO 05/122294, WO05/066156, WO 03/002542, WO 03/030909, WO 00/39101, WO 05/037800 andU.S. Pat. Pub. No. 2003/0149064.

All of the above publications are herein incorporated by reference intheir entirety to the same extent as if each individual publication wasspecifically and individually indicated to be incorporated by referencein its entirety.

III. SUMMARY OF THE INVENTION

This invention is directed to compounds, prodrugs, and methods of usingthese compounds and prodrugs thereof in the treatment of conditions inwhich modulation of the JAK pathway or inhibition of JAK kinases,particularly JAK3, will be therapeutically useful.

In one embodiment, the present invention provides a compound of formulaI, a solvate, prodrug or pharmaceutically acceptable salt thereof:

wherein:

-   -   ring A is aryl or heteroaryl;    -   p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3,        4, or 5 when ring A is bi- or tricyclic;    -   q is 0, 1, 2 or 3;    -   X is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino,        substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro,        alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,        cycloalkynyl and substituted cycloalkynyl;    -   Y is selected from the group consisting of hydrogen,        alk¹-SO₂N(R⁴)R⁵ and alk¹-N(R⁴)SO₂R⁵;    -   W is selected from the group consisting of alk²-SO₂N(R⁶)R⁷ and        alk²-N(R⁶)SO₂R⁷;    -   alk¹ and alk² are each independently a bond, straight or        branched chain C₁₋₆ alkylene group, cycloalkylene or substituted        cycloalkylene wherein:        -   if W is alk²-SO₂N(R⁶)R⁷ and alk² is a bond, then Y is            alk¹-N(R⁴)SO₂R⁵ and alk¹ is a bond;    -   R¹ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkynyl, substituted cycloalkynyl,        cycloalkyl and substituted cycloalkyl;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo and oxo;        -   wherein if R² is oxo then the oxo substituent is attached to            a nonaromatic portion of ring A; or        -   R⁴ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A;    -   Z¹, Z², and Z³ each independently is carbon or nitrogen, wherein        no more than one of Z¹, Z², and Z³ is N; and        -   W is not attached to Z¹, Z² or Z³ when said Z¹, Z² or Z³ is            nitrogen;    -   each R³ independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo, and aminosulfonyl; or        -   R⁶ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to the ring containing Z¹, Z² and Z³; or        -   R⁷ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to the ring containing Z¹, Z² and Z³; or    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen        of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or        -   R⁴ and R⁵ together with the intervening atom or atoms bound            thereto form a heterocyclic or a substituted heterocyclic            group;    -   R⁶ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, carboxyl, carboxyl        ester, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, acyl and M⁺, wherein M⁺ is a counterion selected        from the group consisting of K⁺, Na⁺, Li⁺ or ⁺N(R⁸)₄, wherein R⁸        is hydrogen or alkyl, and the nitrogen of —SO₂N(R⁶)R⁷ or        —N(R⁶)SO₂R⁷ is N⁻; or        -   R⁶ and R⁷ together with the intervening atom or atoms bound            thereto, form a heterocyclic or a substituted heterocyclic            group; or        -   if W is alk²-SO₂N(R⁶)R⁷, then R⁶ and R⁷ together with the            nitrogen atom bound thereto optionally form —N═C(OR⁹)₂            wherein each R⁹ independently is an alkyl group;    -   R⁷ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester,        and acyl;        provided:        when X is hydrogen, ring A is not benzimidazolyl or indazolyl;        and        when W is —CH₂SO₂N(R⁶)R⁷ and ring A is phenyl, then R² cannot be        a —NC(O)R¹⁰, —NC(S)R¹⁰, or —NSO₂R¹⁰ group, where R¹⁰ is an        alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclyl, substituted heterocyclyl, alkoxy, substituted        alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy,        heteroaryl or substituted heteroaryl.

Although M⁺ is preferably a monovalent cation, it can also be a divalentcation with appropriate counterions, for example, two of the parent druganion, one of parent/one of other counter anion, etc.

In another embodiment, the present invention provides a compound offormula III, prodrugs, solvates, or pharmaceutically acceptable saltsthereof:

wherein:

-   -   ring A is aryl or heteroaryl;    -   p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3,        4, or 5 when ring A is bi- or tricyclic;    -   q is 0, 1, 2 or 3;    -   X is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino,        substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro,        alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,        cycloalkynyl and substituted cycloalkynyl;    -   Y is selected from the group consisting of hydrogen,        alk¹-SO₂N(R⁴)R⁵ and alk¹-N(R⁴)SO₂R⁵;    -   alk¹ and alk² are each independently a bond, straight or        branched chain C₁₋₆ alkylene group, cycloalkylene or substituted        cycloalkylene wherein:        -   if alk² is a bond, then Y is alk¹-N(R⁴)SO₂R⁵ and alk¹ is a            bond;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo and oxo;        -   wherein if R² is oxo, then the oxo substituent is attached            to a nonaromatic portion of ring A; or        -   R⁴ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A;    -   each R³ independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        substituted alkynyl, cycloalkynyl, substituted cycloalkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo, and aminosulfonyl; or        -   R⁶ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic;            or        -   R⁷ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic;            or    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen        of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or        -   R⁴ and R⁵ together with the intervening atom or atoms bound            thereto form a heterocyclic or a substituted heterocyclic            group;    -   R⁶ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, carboxyl, carboxyl        ester, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, acyl and M⁺, wherein M⁺ is a counterion selected        from the group consisting of K⁺, Na⁺, Li⁺ or ⁺N(R⁸)₄, wherein R⁸        is hydrogen or alkyl, and the nitrogen of —SO₂N(R⁶)R⁷ or        —N(R⁶)SO₂R⁷ is N⁻; or        -   R⁶ and R⁷ together with the intervening atom or atoms bound            thereto, form a heterocyclic or a substituted heterocyclic            group; or    -   R⁷ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester,        and acyl;        provided:        when X is hydrogen, ring A is not benzimidazolyl or indazolyl;        and        when alk² is —CH₂ and ring A is phenyl, then R² cannot be a        —NC(O)R¹⁰, —NC(S)R¹⁰, or —NSO₂R¹⁰ group, where R¹⁰ is an alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclyl, substituted heterocyclyl, alkoxy, substituted        alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy,        heteroaryl or substituted heteroaryl.

Although M⁺ is preferably a monovalent cation, it can also be a divalentcation with appropriate counterions, for example, two of the parent druganion, one of parent/one of other counter anion, etc.

In another embodiment, this invention provides a compound of formula IV,prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein:

-   -   ring A is aryl or heteroaryl;    -   p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3,        4, or 5 when ring A is bi- or tricyclic;    -   q is 0, 1, 2 or 3;    -   X is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino,        substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro,        alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,        cycloalkynyl and substituted cycloalkynyl;    -   Y is selected from the group consisting of hydrogen,        alk¹-SO₂N(R⁴)R⁵ and alk¹-N(R⁴)SO₂R⁵;    -   alk¹ and alk² are each independently a bond or a straight or        branched chain C₁₋₆ alkylene group;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo and oxo;        -   wherein if R² is oxo, then the oxo substituent is attached            to a nonaromatic portion of ring A; or        -   R⁴ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A;    -   each R³ independently is selected from the group consisting of        is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl,        cycloalkynyl, substituted cycloalkynyl, alkynyloxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro, halo, and aminosulfonyl; or        -   R⁶ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic;            or        -   R⁷ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic;            or    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen        of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or        -   R⁴ and R⁵ together with the intervening atom or atoms bound            thereto form a heterocyclic or a substituted heterocyclic            group;    -   R⁶ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, carboxyl, carboxyl        ester, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, acyl and M⁺, wherein M⁺ is a counterion selected        from the group consisting of K⁺, Na⁺, Li⁺ or ⁺N(R⁸)₄, wherein R⁸        is hydrogen or alkyl, and the nitrogen of —SO₂N(R⁶)R⁷ or        —N(R⁶)SO₂R⁷ is N⁻; or        -   R⁶ and R⁷ together with the intervening atom or atoms bound            thereto, form a heterocyclic or a substituted heterocyclic            group; or    -   R⁷ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester,        and acyl;        provided:        when X is hydrogen, ring A is not benzimidazolyl or indazolyl;        and        when alk² is —CH₂ and ring A is phenyl, then R² cannot be a        —NC(O)R¹⁰, —NC(S)R¹⁰, or —NSO₂R¹⁰ group, where R¹⁰ is an alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclyl, substituted heterocyclyl, alkoxy, substituted        alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy,        heteroaryl or substituted heteroaryl.

Although M⁺ is preferably a monovalent cation, it can also be a divalentcation with appropriate counterions, for example, two of the parent druganion, one of parent/one of other counter anion, etc.

In another embodiment, this invention provides a compound of formula VI,prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein:

-   -   p is 0, 1, 2 or 3;    -   q is 0, 1, 2 or 3;    -   X is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino,        substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro,        alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,        cycloalkynyl and substituted cycloalkynyl;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo and oxo;        -   wherein if R² is oxo, then the oxo substituent is attached            to a nonaromatic portion of ring A; or    -   R⁴ and one of R² together with the intervening atoms bound        thereto form a heterocyclic or a substituted heterocyclic fused        to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A;    -   each R³ independently is selected from the group consisting of        is selected from the group consisting of alkyl, substituted        alkyl, alkoxy, substituted alkoxy, alkynyl, substituted alkynyl,        cycloalkynyl, substituted cycloalkynyl, alkynyloxy, amino,        substituted amino, aryl, substituted aryl, aryloxy, substituted        aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy,        substituted cycloalkoxy, heteroaryl, substituted heteroaryl,        heteroaryloxy, substituted heteroaryloxy, heterocyclic,        substituted heterocyclic, heterocyclyloxy, substituted        heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl        ester, carbonate ester, nitro, halo and aminosulfonyl;    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen        of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or        -   R⁴ and R⁵ together with the intervening atom or atoms bound            thereto form a heterocyclic or a substituted heterocyclic            group.

Although M⁺ is preferably a monovalent cation, it can also be a divalentcation with appropriate counterions, for example, two of the parent druganion, one of parent/one of other counter anion, etc.

In another embodiment, this invention provides a method of inhibiting anactivity of a JAK kinase, comprising contacting the JAK kinase with anamount of a compound effective to inhibit an activity of the JAK kinasewherein the compound is selected from the compounds of this invention,as described above.

In another embodiment, this invention provides a method of inhibiting anactivity of a JAK kinase, comprising contacting in vitro a JAK3 kinasewith an amount of a compound effective to inhibit an activity of the JAKkinase wherein the compound is selected from the compounds of thisinvention, as described above.

In another embodiment, this invention provides a method of inhibiting anactivity of a JAK kinase, comprising contacting in a cell a JAK3 kinasewith an amount of a compound effective to inhibit an activity of the JAKkinase wherein the compound is selected from the compounds of thisinvention, as described above.

In another embodiment, this invention provides a method of treating aT-cell mediated autoimmune disease, comprising administering to apatient suffering from such an autoimmune disease an amount of acompound effective to treat the autoimmune disease wherein the compoundis selected from the compounds of this invention, as described above.

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient,comprising administering to the transplant recipient an amount of acompound effective to treat or prevent the rejection wherein thecompound is selected from the compounds of this invention, as describedabove.

In another embodiment, this invention provides a method of treating orpreventing a Type IV hypersensitivity reaction, comprising administeringto a subject an amount of a compound of effective to treat or preventthe hypersensitivity reaction wherein the compound is selected from thecompounds of this invention, as described above.

In another embodiment, this invention provides a method of inhibiting asignal transduction cascade in which JAK3 kinase plays a role,comprising contacting a cell expressing a receptor involved in such asignaling cascade with a compound wherein the compound is selected fromthe compounds of this invention, as described above.

In another embodiment, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease wherein the compound is selected from thecompounds of this invention, as described above.

In another embodiment, this invention provides a pharmaceuticalformulation comprising a compound selected from the compounds of thisinvention, as described above. In another embodiment, this inventionprovides a kit comprising a compound selected from the compounds of thisinvention packaging, and instructions for use.

IV. DETAILED DESCRIPTION a. Overview

The invention encompasses compounds having formula I and thecompositions and methods using these compounds in the treatment ofconditions in which modulation of the JAK pathway or inhibition of JAKkinases, particularly JAK3, can be therapeutically useful.

wherein ring A, R¹, (R²)_(p), (R³)_(q), W, X, Y, Z¹, Z² and Z³ are asdefined above.

b. Definitions

As used herein, the following definitions shall apply unless otherwiseindicated.

“Alkyl” refers to monovalent saturated aliphatic hydrocarbyl groupshaving from 1 to 10 carbon atoms and preferably 1 to 6 carbon atoms.This term includes, by way of example, linear and branched hydrocarbylgroups such as methyl (CH₃—), ethyl (CH₃CH₂—), n-propyl (CH₃CH₂CH₂—),isopropyl ((CH₃)₂CH—), n-butyl (CH₃CH₂CH₂CH₂—), isobutyl ((CH₃)₂CHCH₂—),sec-butyl ((CH₃)(CH₃CH₂)CH—), t-butyl ((CH₃)₃C—), n-pentyl(CH₃CH₂CH₂CH₂CH₂—), and neopentyl ((CH₃)₃CCH₂—).

“Substituted alkyl” refers to an alkyl group having from 1 to 5hydrogens replaced with substituents selected from the group consistingof alkoxy, substituted alkoxy, acyl, acylamino, acyloxy, amino,substituted amino, aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, alkynyl, substitutedalkynyl, cycloalkynyl, substituted cycloalkynyl guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents aredefined herein. In some embodiments, the alkyl has 1 to 3 of theaforementioned groups. In other embodiments, the alkyl has 1 to 2 of theaforementioned groups.

“Alkylene” refers to divalent saturated aliphatic hydrocarbyl groupspreferably having from 1 to 6 and more preferably 1 to 3 carbon atomsthat are either straight-chained or branched. This term is exemplifiedby groups such as methylene (—CH₂—), ethylene (—CH₂CH₂—), n-propylene(—CH₂CH₂CH₂—), iso-propylene (—CH₂CH(CH₃)—) or (—CH(CH₃)CH₂—), and thelike.

“Substituted alkylene” refers to an alkylene group having from 1 to 3hydrogens replaced with substituents selected from the group consistingof alkyl, substituted alkyl, alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl,substituted aryl, aryloxy, substituted aryloxy, cyano, halogen,hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, and oxo wherein said substituents are definedherein. In some embodiments, the alkylene has 1 to 2 of theaforementioned groups. It is to be noted that when the alkylene issubstituted by an oxo group, 2 hydrogens attached to the same carbon ofthe alkylene group are replaced by “═O”.

“Alkoxy” refers to the group —O-alkyl, wherein alkyl is as definedherein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like.

“Substituted alkoxy” refers to the group —O-(substituted alkyl), whereinsubstituted alkyl is as defined herein.

“Acyl” refers to the groups H—C(O)—, alkyl-C(O)—, substitutedalkyl-C(O)—, alkenyl-C(O)—, substituted alkenyl-C(O)—, alkynyl-C(O)—,substituted alkynyl-C(O)-cycloalkyl-C(O)—, substituted cycloalkyl-C(O)—,cycloalkenyl-C(O)—, substituted cycloalkenyl-C(O)—, aryl-C(O)—,substituted aryl-C(O)—, heteroaryl-C(O)—, substituted heteroaryl-C(O)—,heterocyclic-C(O)—, and substituted heterocyclic-C(O)—, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein. Acyl includes the “acetyl” group CH₃C(O)—.

“Acylamino” refers to the groups —NR²⁰C(O)alkyl, —NR²⁰C(O)substitutedalkyl, —NR²⁰C(O)cycloalkyl, —NR²⁰C(O)substituted cycloalkyl,—NR²⁰C(O)cycloalkenyl, —NR²⁰C(O)substituted cycloalkenyl,—NR²⁰C(O)alkenyl, —NR²⁰C(O)substituted alkenyl, —NR²⁰C(O)alkynyl,—NR²⁰C(O)substituted alkynyl, —NR²⁰C(O)aryl, —NR²⁰C(O)substituted aryl,—NR²⁰C(O)heteroaryl, —NR²⁰C(O)substituted heteroaryl,—NR²⁰C(O)heterocyclic, and —NR²⁰C(O)substituted heterocyclic, whereinR²⁰ is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Acyloxy” refers to the groups alkyl-C(O)O—, substituted alkyl-C(O)O—,alkenyl-C(O)O—, substituted alkenyl-C(O)O—, alkynyl-C(O)O—, substitutedalkynyl-C(O)O—, aryl-C(O)O—, substituted aryl-C(O)O—, cycloalkyl-C(O)O—,substituted cycloalkyl-C(O)O—, cycloalkenyl-C(O)O—, substitutedcycloalkenyl-C(O)O—, heteroaryl-C(O)O—, substituted heteroaryl-C(O)O—,heterocyclic-C(O)O—, and substituted heterocyclic-C(O)O—, wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Amino” refers to the group —NH₂.

“Substituted amino” refers to the group —NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic, where one of R²¹ andR²² is sulfonyl, and wherein R²¹ and R²² are optionally joined togetherwith the nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, provided that R²¹ and R²² are not both hydrogen, andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, sulfonyl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein. When R²¹ is hydrogen and R²² is alkyl, thesubstituted amino group is sometimes referred to herein as “alkylamino.”When R²¹ and R²² are alkyl, the substituted amino group is sometimesreferred to herein as “dialkylamino.” When referring to amonosubstituted amino, it is meant that either R²¹ or R²² is hydrogen,but not both. When referring to a disubstituted amino, it is meant thatneither R²¹ nor R²² is hydrogen.

“Aminoacyl” or “Aminocarbonyl” refers to the group —C(O)NR²¹R²², whereinR²¹ and R²² independently are selected from the group consisting ofhydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R²¹ and R²² are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Aminothiocarbonyl” refers to the group —C(S)NR²¹R²², wherein R²¹ andR²² independently are selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic andwhere R²¹ and R²² are optionally joined together with the nitrogen boundthereto to form a heterocyclic or substituted heterocyclic group, andwherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“Aminocarbonylamino” refers to the group —NR²⁰C(O)NR²¹R²², wherein R²⁰is hydrogen or alkyl and R²¹ and R²² independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminothiocarbonylamino” refers to the group —NR²⁰C(S)NR²¹R²², whereinR²⁰ is hydrogen or alkyl and R²¹ and R²² independently are selected fromthe group consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminoacyloxy” or “Aminocarbonyloxy” refers to the group —O—C(O)NR²¹R²²,wherein R²¹ and R²² independently are selected from the group consistingof hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic and where R²¹ and R²² are optionally joined together withthe nitrogen bound thereto to form a heterocyclic or substitutedheterocyclic group, and wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Aminosulfonyl” refers to the group —SO₂NR²¹R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, substituted heterocyclic and where R²¹ and R²²are optionally joined together with the nitrogen bound thereto to form aheterocyclic or substituted heterocyclic group and alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic and substituted heterocyclic are as definedherein.

“Aminosulfonyloxy” refers to the group —O—SO₂NR²¹R²², wherein R²¹ andR²² independently are selected from the group consisting of hydrogen,alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, aryl, substituted aryl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic; R²¹and R²² are optionally joined together with the nitrogen bound theretoto form a heterocyclic or substituted heterocyclic group; and alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Aminosulfonylamino” refers to the group —NR²⁰—SO₂NR²¹R²², wherein R²⁰is hydrogen or alkyl and R²¹ and R²² independently are selected from thegroup consisting of hydrogen, alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, aryl, substitutedaryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic and where R²¹ and R²² are optionally joinedtogether with the nitrogen bound thereto to form a heterocyclic orsubstituted heterocyclic group, and wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic andsubstituted heterocyclic are as defined herein.

“Sulfonylamino” refers to the group —NR²¹SO₂R²², wherein R²¹ and R²²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R²¹ andR²² are optionally joined together with the atoms bound thereto to forma heterocyclic or substituted heterocyclic group, and wherein alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, aryl, substituted aryl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic are as definedherein.

“Amidino” refers to the group —C(═NR³⁰)NR³¹R³², wherein R³¹ and R³²independently are selected from the group consisting of hydrogen, alkyl,substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substitutedalkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl,cycloalkenyl, substituted cycloalkenyl, heteroaryl, substitutedheteroaryl, heterocyclic, and substituted heterocyclic and where R³¹ andR³² are optionally joined together with the nitrogen bound thereto toform a heterocyclic or substituted heterocyclic group R³⁰ is selectedfrom the group consisting of hydrogen, alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkynyl, substituted cycloalkynyl, aryl, substituted aryl,cycloalkyl, substituted cycloalkyl, cycloalkenyl, substitutedcycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, nitro, nitroso, hydroxy, alkoxy, cyano,—N═N—N-alkyl, —N═N—N-substituted alkyl, —N(alkyl)SO₂-alkyl,—N(alkyl)SO₂-substituted alkyl, —N═N═N-alkyl, —N═N═N-substituted alkyl,acyl, —SO₂-alkyl and —SO₂-substituted alkyl, wherein alkyl, substitutedalkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,cycloalkynyl, substituted cycloalkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, substitutedheterocyclic, nitro, nitroso, hydroxy, alkoxy, and cyano are as definedherein.

“Aryl” or “Ar” refers to a monovalent aromatic carbocyclic group of from6 to 14 carbon atoms having a single ring (e.g., phenyl) or multiplecondensed rings (e.g., naphthyl or anthryl) which condensed rings may ormay not be aromatic (e.g., 2-benzoxazolinone,2H-1,4-benzoxazin-3(4H)-one-7-yl, and the like), provided that the pointof attachment is through an atom of the aromatic aryl group. Preferredaryl groups include phenyl and naphthyl.

“Substituted aryl” refers to aryl groups having 1 to 5 hydrogensreplaced with substituents independently selected from the groupconsisting of alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminocarbonyl,aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino,amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio,substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino,(carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substitutedcycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy,substituted cycloalkenyloxy, cycloalkenylthio, substitutedcycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy,heteroaryl, substituted heteroaryl, heteroaryloxy, substitutedheteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are as defined herein. In some embodiments,the aryl has 1 to 3 of the aforementioned groups. In other embodiments,the aryl has 1 to 2 of the aforementioned groups.

“Aryloxy” refers to the group —O-aryl, wherein aryl is as definedherein, including, by way of example, phenoxy, naphthoxy, and the like.

“Substituted aryloxy” refers to the group —O-(substituted aryl), whereinsubstituted aryl is as defined herein.

“Arylthio” refers to the group —S-aryl, wherein aryl is as definedherein. In other embodiments, sulfur may be oxidized to —S(O)— or —SO₂—moieties. The sulfoxide may exist as one or more stereoisomers.

“Substituted arylthio” refers to the group —S-(substituted aryl),wherein substituted aryl is as defined herein. In other embodiments,sulfur may be oxidized to —S(O)— or —SO₂— moieties. The sulfoxide mayexist as one or more stereoisomers.

“Alkenyl” refers to monovalent unsaturated hydrocarbyl groups havingfrom 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and havingat least 1 and preferably from 1 to 2 sites of unsaturation. Such groupsare exemplified by vinyl, allyl, but-3-en-1-yl, and the like.

“Substituted alkenyl” refers to alkenyl groups having from 1 to 3substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents are asdefined herein and with the proviso that any hydroxy substitution is notattached to a vinyl (unsaturated) carbon atom. In some embodiments, thealkenyl has 1 to 2 of the aforementioned groups.

“Alkenylene” refers to divalent unsaturated straight chain or branchedchain hydrocarbyl groups having from 2 to 10 carbon atoms and preferably2 to 6 carbon atoms and having at least 1 and preferably from 1-2 sitesof double bond unsaturation. The term “alkenylene” encompasses any andall combinations of cis and trans isomers arising from the presence ofunsaturation. “Substituted alkenylene” refers to divalent alkenylenegroups having from 1 to 3 substituents selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,acyl, acylamino, amino, substituted amino, aminoacyl, aryl, substitutedaryl, aryloxy, substituted aryloxy, cyano, halogen, hydroxyl, nitro,carboxyl, carboxyl esters, cycloalkyl, substituted cycloalkyl,heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic, provided that any hydroxy or thiol substitution is not ona double bond carbon. In some embodiments, the alkenylene has 1 to 2 ofthe aforementioned groups.

“Alkynyl” refers to monovalent unsaturated hydrocarbyl groups havingfrom 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and havingat least 1 and preferably from 1 to 2 sites of triple bond unsaturation.

“Substituted alkynyl” refers to alkynyl groups having from 1 to 3substituents selected from the group consisting of alkoxy, substitutedalkoxy, acyl, acylamino, acyloxy, amino, substituted amino,aminocarbonyl, aminothiocarbonyl, aminocarbonylamino,aminothiocarbonylamino, aminocarbonyloxy, aminosulfonyl,aminosulfonyloxy, aminosulfonylamino, amidino, aryl, substituted aryl,aryloxy, substituted aryloxy, arylthio, substituted arylthio, carboxyl,carboxyl ester, (carboxyl ester)amino, (carboxyl ester)oxy, cyano,cycloalkyl, substituted cycloalkyl, cycloalkyloxy, substitutedcycloalkyloxy, cycloalkylthio, substituted cycloalkylthio, cycloalkenyl,substituted cycloalkenyl, cycloalkenyloxy, substituted cycloalkenyloxy,cycloalkenylthio, substituted cycloalkenylthio, guanidino, substitutedguanidino, halo, hydroxy, heteroaryl, substituted heteroaryl,heteroaryloxy, substituted heteroaryloxy, heteroarylthio, substitutedheteroarylthio, heterocyclic, substituted heterocyclic, heterocyclyloxy,substituted heterocyclyloxy, heterocyclylthio, substitutedheterocyclylthio, nitro, SO₃H, sulfonyl, sulfonyloxy, thioacyl, thiol,alkylthio, and substituted alkylthio, wherein said substituents are asdefined herein and with the proviso that any hydroxy or thiolsubstitution is not attached to an acetylenic carbon atom. In someembodiments, the alkynyl has 1 to 2 of the aforementioned groups.

“Alkynyloxy” refers to the group —O-alkynyl, wherein alkynyl is asdefined herein. Alkynyloxy includes, by way of example, ethynyloxy,propynyloxy, and the like.

“Carboxyl” or “carboxy” refers to —COOH or salts thereof.

“Carboxyl ester” or “carboxy ester” refers to the groups —C(O)O-alkyl,—C(O)O-substituted alkyl, —C(O)O-alkenyl, —C(O)O-substituted alkenyl,—C(O)O-alkynyl, —C(O)O-substituted alkynyl, —C(O)O-aryl,—C(O)O-substituted aryl, —C(O)β-cycloalkyl, —C(O)O-substitutedcycloalkyl, —C(O)β-cycloalkenyl, —C(O)O-substituted cycloalkenyl,—C(O)O-heteroaryl, —C(O)O-substituted heteroaryl, —C(O)O-heterocyclic,and —C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl,alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“(Carboxyl ester)amino” refers to the groups —NR—C(O)O-alkyl,—NR—C(O)O-substituted alkyl, —NR—C(O)O-alkenyl, —NR—C(O)O-substitutedalkenyl, —NR—C(O)O-alkynyl, —NR—C(O)O-substituted alkynyl,—NR—C(O)O-aryl, —NR—C(O)O-substituted aryl, —NR—C(O)β-cycloalkyl,—NR—C(O)O-substituted cycloalkyl, —NR—C(O)β-cycloalkenyl,—NR—C(O)O-substituted cycloalkenyl, —NR—C(O)O-heteroaryl,—NR—C(O)O-substituted heteroaryl, —NR—C(O)O-heterocyclic, and—NR—C(O)O-substituted heterocyclic, wherein R is alkyl or hydrogen andalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“(Carboxyl ester)oxy” refers to the groups —O—C(O)O-alkyl,—O—C(O)O-substituted alkyl, —O—C(O)O-alkenyl, —O—C(O)O-substitutedalkenyl, —O—C(O)O-alkynyl, —O—C(O)O-substituted alkynyl, —O—C(O)O-aryl,—O—C(O)O-substituted aryl, —O—C(O)β-cycloalkyl, —O—C(O)O-substitutedcycloalkyl, —O—C(O)β-cycloalkenyl, —O—C(O)O-substituted cycloalkenyl,—O—C(O)O-heteroaryl, —O—C(O)O-substituted heteroaryl,—O—C(O)O-heterocyclic, and —O—C(O)O-substituted heterocyclic, whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“Carbonate ester” refers to the groups —OC(O)O-alkyl,—OC(O)O-substituted alkyl, —OC(O)O-alkenyl, —OC(O)O-substituted alkenyl,—OC(O)O-alkynyl, —OC(O)O-substituted alkynyl, —OC(O)O-aryl,—OC(O)O-substituted aryl, —OC(O)β-cycloalkyl, —OC(O)O-substitutedcycloalkyl, —OC(O)β-cycloalkenyl, —OC(O)O-substituted cycloalkenyl,—OC(O)O-heteroaryl, —OC(O)O-substituted heteroaryl,—OC(O)O-heterocyclic, and —OC(O)O-substituted heterocyclic, whereinalkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl,substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic areas defined herein.

“Cyano” or “nitrile” refers to the group —CN.

“Cycloalkyl” refers to cyclic alkyl groups of from 3 to 10 carbon atomshaving single or multiple cyclic rings including fused, bridged, andspiro ring systems. Examples of suitable cycloalkyl groups include, forinstance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyland the like.

“Cycloalkenyl” refers to non-aromatic cyclic alkyl groups of from 3 to10 carbon atoms having single or multiple rings and having at least onedouble bond and preferably from 1 to 2 double bonds.

“Cycloalkynyl” refers to non-aromatic cycloalkyl groups of from 5 to 10carbon atoms having single or multiple rings and having at least onetriple bond.

“Cycloalkylene” refers to divalent cycloalkyl groups, wherein cycloalkylis as defined herein.

“Substituted cycloalkylene” refers to cycloalkylene group having from 1to 3 hydrogens replaced with substituents selected from the groupconsisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy,acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aryl,substituted aryl, aryloxy, substituted aryloxy, cyano, halogen,hydroxyl, nitro, carboxyl, carboxyl ester, cycloalkyl, substitutedcycloalkyl, heteroaryl, substituted heteroaryl, heterocyclic,substituted heterocyclic, and oxo wherein said substituents are asdefined herein. In some embodiments, the alkylene has 1 to 2 of theaforementioned groups. It is to be noted that when the cycloalkylene issubstituted by an oxo group, 2 hydrogens attached to the same carbon ofthe cycloalkylene group are replaced by “═O”.

“Substituted cycloalkyl,” “substituted cycloalkenyl,” and “substitutedcycloalkynyl” refer to a cycloalkyl, cycloalkenyl, or cycloalkynyl grouphaving from 1 to 5 substituents selected from the group consisting ofoxo, thioxo, alkyl, substituted alkyl, alkenyl, substituted alkenyl,alkynyl, substituted alkynyl, alkoxy, substituted alkoxy, acyl,acylamino, acyloxy, amino, substituted amino, aminocarbonyl,aminothiocarbonyl, aminocarbonylamino, aminothiocarbonylamino,aminocarbonyloxy, aminosulfonyl, aminosulfonyloxy, aminosulfonylamino,amidino, aryl, substituted aryl, aryloxy, substituted aryloxy, arylthio,substituted arylthio, carboxyl, carboxyl ester, (carboxyl ester)amino,(carboxyl ester)oxy, cyano, cycloalkyl, substituted cycloalkyl,cycloalkyloxy, substituted cycloalkyloxy, cycloalkylthio, substitutedcycloalkylthio, cycloalkenyl, substituted cycloalkenyl, cycloalkenyloxy,substituted cycloalkenyloxy, cycloalkenylthio, substitutedcycloalkenylthio, guanidino, substituted guanidino, halo, hydroxy,heteroaryl, substituted heteroaryl, heteroaryloxy, substitutedheteroaryloxy, heteroarylthio, substituted heteroarylthio, heterocyclic,substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy,heterocyclylthio, substituted heterocyclylthio, nitro, SO₃H, sulfonyl,sulfonyloxy, thioacyl, thiol, alkylthio, and substituted alkylthio,wherein said substituents are as defined herein, provides that anyhydroxy or thiol substitution is not attached to an unsaturated carbonatom. In some embodiments, the cycloalkyl or cycloalkenyl has 1 to 3 ofthe aforementioned groups. In some embodiments, the cycloalkyl group mayhave multiple condensed rings (e.g. tetrahydronaphthyl ortetrahydroanthacenyl), provided that the point of attachment is throughan atom of the nonaromatic ring.

“Cycloalkoxy” refers to —O-cycloalkyl.

“Substituted cycloalkoxy” refers to —O-(substituted cycloalkyl).

“Cycloalkylthio” refers to —S-cycloalkyl. In other embodiments, sulfurmay be oxidized to —S(O)— or —SO₂— moieties. The sulfoxide may exist asone or more stereoisomers.

“Substituted cycloalkylthio” refers to —S-(substituted cycloalkyl). Inother embodiments, sulfur may be oxidized to —S(O)—, or —SO₂— moieties.The sulfoxide may exist as one or more stereoisomers.

“Cycloalkenyloxy” refers to —O-cycloalkenyl.

“Substituted cycloalkenyloxy” refers to —O-(substituted cycloalkenyl).

“Cycloalkenylthio” refers to —S-cycloalkenyl. In other embodiments,sulfur may be oxidized to sulfonyl or sulfonyl moieties. The sulfoxidemay exist as one or more stereoisomers.

“Substituted cycloalkenylthio” refers to —S-(substituted cycloalkenyl).In other embodiments, sulfur may be oxidized to —S(O)— or —SO₂—moieties. The sulfoxide may exist as one or more stereoisomers.

“Guanidino” refers to the group —NHC(═NH)NH₂.

“Substituted guanidino” refers to the group —NR³³C(═NR³³)N(R³³)₂,wherein each R³³ independently is selected from the group consisting ofhydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl,substituted heteroaryl, heterocyclic, and substituted heterocyclic; twoR groups attached to a common guanidino nitrogen atom are optionallyjoined together with the nitrogen bound thereto to form a heterocyclicor substituted heterocyclic group, provided that at least one R is nothydrogen; and said substituents are as defined herein.

“Halo” or “halogen” refers to fluoro, chloro, bromo, and iodo and ispreferably fluoro or chloro.

“Hydroxy” or “hydroxyl” refers to the group —OH.

“Heteroaryl” refers to an aromatic group of from 1 to 10 carbon atomsand 1 to 4 heteroatoms selected from the group consisting of oxygen,nitrogen, and sulfur within the ring. Such heteroaryl groups can have asingle ring (e.g., pyridinyl or furyl) or multiple condensed rings(e.g., indolizinyl or benzothienyl), wherein the condensed rings may ormay not be aromatic and/or contain a heteroatom, provided that the pointof attachment is through an atom of the aromatic heteroaryl group. Inone embodiment, the nitrogen and/or sulfur ring atom(s) of theheteroaryl group are optionally oxidized to provide for the N-oxide(N→O), sulfinyl, or sulfonyl moieties. Preferred heteroaryls includepyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl.

“Substituted heteroaryl” refers to heteroaryl groups that aresubstituted with from 1 to 5 substituents selected from the groupconsisting of the same group of substituents defined for substitutedaryl. In some embodiments, the heteroaryl has 1 to 3 of theaforementioned groups. In other embodiments, the heteroaryl has 1 to 2of the aforementioned groups.

“Heteroaryloxy” refers to —O-heteroaryl.

“Substituted heteroaryloxy” refers to the group —O-(substitutedheteroaryl).

“Heteroarylthio” refers to the group —S-heteroaryl. In otherembodiments, sulfur may be oxidized to —S(O)— or —SO₂— moieties. Thesulfoxide may exist as one or more stereoisomers.

“Substituted heteroarylthio” refers to the group —S-(substitutedheteroaryl). In other embodiments, sulfur may be oxidized to —S(O)— or—SO₂— moieties. The sulfoxide may exist as one or more stereoisomers.

“Heterocycle,” “heterocyclic,” “heterocycloalkyl,” and “heterocyclyl”refer to a saturated or unsaturated group having a single ring ormultiple condensed rings, including fused bridged and spiro ringsystems, and having from 3 to 15 ring atoms, including 1 to 4 heteroatoms. These ring atoms are selected from the group consisting ofnitrogen, sulfur, or oxygen, wherein, in fused ring systems, one or moreof the rings can be cycloalkyl, aryl, or heteroaryl, provided that thepoint of attachment is through the non-aromatic ring. In one embodiment,the nitrogen and/or sulfur atom(s) of the heterocyclic group areoptionally oxidized to provide for the N-oxide, —S(O)—, or —SO₂—moieties.

“Substituted heterocyclic,” “substituted heterocycloalkyl,” and“substituted heterocyclyl” refer to heterocyclyl groups that aresubstituted with from 1 to 5 of the same substituents as defined forsubstituted cycloalkyl. In some embodiments, the heterocyclyl has 1 to 3of the aforementioned groups.

“Heterocyclyloxy” refers to the group —O-heterocycyl.

“Substituted heterocyclyloxy” refers to the group —O-(substitutedheterocycyl).

“Heterocyclylthio” refers to the group —S-heterocycyl. In otherembodiments, sulfur may be oxidized to —S(O)— or —SO₂— moieties. Thesulfoxide may exist as one or more stereoisomers.

“Substituted heterocyclylthio” refers to the group —S-(substitutedheterocycyl). In other embodiments, sulfur may be oxidized to —S(O)— or—SO₂— moieties. The sulfoxide may exist as one or more stereoisomers.

Examples of heterocycle and heteroaryls include, but are not limited to,azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine,pyridazine, indolizine, isoindole, indole, dihydroindole, indazole,purine, quinolizine, isoquinoline, quinoline, phthalazine,naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine,carbazole, carboline, phenanthridine, acridine, phenanthroline,isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine,imidazolidine, imidazoline, piperidine, piperazine, indoline,phthalimide, 1,2,3,4-tetrahydroisoquinoline,4,5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene,benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to asthiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine,tetrahydrofuranyl, and the like.

“Nitro” refers to the group —NO₂.

“Nitroso” refers to the group —NO.

“Oxo” refers to the atom (═O).

“Sulfonyl” refers to the group —SO₂-alkyl, —SO₂-substituted alkyl,—SO₂-alkenyl, —SO₂-substituted alkenyl, —SO₂-cycloalkyl,—SO₂-substituted cycloalkyl, —SO₂-cycloalkenyl, —SO₂-substitutedcycloalkenyl, —SO₂-aryl, —SO₂-substituted aryl, —SO₂-heteroaryl,—SO₂-substituted heteroaryl, —SO₂-heterocyclic, and —SO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein. Sulfonyl includes groups such asmethyl-SO₂—, phenyl-SO₂—, and 4-methylphenyl-SO₂—.

“Sulfonyloxy” refers to the group —OSO₂-alkyl, —OSO₂-substituted alkyl,—OSO₂-alkenyl, —OSO₂-substituted alkenyl, —OSO₂-cycloalkyl,—OSO₂-substituted cycloalkyl, —OSO₂-cycloalkenyl, —OSO₂-substitutedcycloalkenyl, —OSO₂-aryl, —OSO₂-substituted aryl, —OSO₂-heteroaryl,—OSO₂-substituted heteroaryl, —OSO₂-heterocyclic, and —OSO₂-substitutedheterocyclic, wherein alkyl, substituted alkyl, alkenyl, substitutedalkenyl, alkynyl, substituted alkynyl, cycloalkyl, substitutedcycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substitutedaryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein.

“Thioacyl” refers to the groups H—C(S)—, alkyl-C(S)—, substitutedalkyl-C(S)—, alkenyl-C(S)—, substituted alkenyl-C(S)—, alkynyl-C(S)—,substituted alkynyl-C(S)—, cycloalkyl-C(S)—, substitutedcycloalkyl-C(S)—, cycloalkenyl-C(S)—, substituted cycloalkenyl-C(S)—,aryl-C(S)—, substituted aryl-C(S)—, heteroaryl-C(S)—, substitutedheteroaryl-C(S)—, heterocyclic-C(S)—, and substitutedheterocyclic-C(S)—, wherein alkyl, substituted alkyl, alkenyl,substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl,substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl,substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, andsubstituted heterocyclic are as defined herein.

“Thiol” refers to the group —SH.

“Thioxo” refers to the atom (═S).

“Alkylthio” refers to the group —S-alkyl, wherein alkyl is as definedherein. In other embodiments, sulfur may be oxidized to —S(O)—. Thesulfoxide may exist as one or more stereoisomers.

“Substituted alkylthio” refers to the group —S-(substituted alkyl),wherein substituted alkyl is as defined herein. In other embodiments,sulfur may be oxidized to —S(O)—. The sulfoxide may exist as one or morestereoisomers.

“Stereoisomer” and “stereoisomers” refer to compounds that differ in thechirality of one or more stereocenters. Stereoisomers includeenantiomers and diastereomers.

“Tautomer” refers to alternate forms of a molecule that differ in theposition of a proton, such as enol-keto and imine-enamine tautomers, orthe tautomeric forms of heteroaryl groups containing a —N═C(H)—NH— ringatom arrangement, such as pyrazoles, imidazoles, benzimidazoles,triazoles, and tetrazoles. A person of ordinary skill in the art wouldrecognize that other tautomeric ring atom arrangements are possible.

“Patient” refers to human and non-human animals, especially mammals.

“Pharmaceutically acceptable salt” refers to pharmaceutically acceptablesalts of a compound, which salts are derived from a variety of organicand inorganic counter ions well known in the art and include, by way ofexample only, sodium, potassium, calcium, magnesium, ammonium,tetraalkylammonium, and the like; and when the molecule contains a basicfunctionality, salts of organic or inorganic acids, such ashydrochloride, hydrobromide, tartrate, mesylate, acetate, maleate,oxalate, and the like.

“Prodrug” refers to a derivative of an active 4-pyrimidineamine compound(drug) that may require a transformation under the conditions of use,such as within the body, to release the active 2,4-pyrimidinediaminedrug. Prodrugs are frequently, but not necessarily, pharmacologicallyinactive until converted into the active drug. Prodrugs are typicallyobtained by masking one or more functional groups in an active2,4-pyrimidinediamine drug believed to be in part required for activitywith a progroup (defined below) to form a promoiety which undergoes atransformation, such as cleavage, under the specified conditions of useto release the functional group, and hence the active2,4-pyrimidinediamine drug. The cleavage of the promoiety may proceedspontaneously, such as by way of a hydrolysis reaction, or it can becatalyzed or induced by another agent, such as an enzyme, light, an acidor base, or a change of or exposure to a physical or environmentalparameter, such as temperature. The agent can be endogenous to theconditions of use, such as an enzyme present in the cells to which theprodrug is administered or the acidic conditions of the stomach, or itcan be supplied exogenously.

“Progroup” refers to a type of protecting group that, when used to maska functional group within an active 2,4-pyrimidinediamine drug to form apromoiety, converts the drug into a prodrug. Progroups are typicallyattached to the functional group of the drug via bonds that arecleavable under specified conditions of use. Thus, a progroup is thatportion of a promoiety that cleaves to release the functional groupunder the specified conditions of use. As a specific example, an amidepromoiety of the formula —NH—C(O)CH₃ comprises the progroup —C(O)CH₃.

“Pharmaceutically effective amount” and “therapeutically effectiveamount” refer to an amount of a compound sufficient to treat a specifieddisorder or disease or one or more of its symptoms and/or to prevent theoccurrence of the disease or disorder. In reference to tumorigenicproliferative disorders, a pharmaceutically or therapeutically effectiveamount comprises an amount sufficient to, among other things, cause thetumor to shrink or decrease the growth rate of the tumor.

“Solvate” refers to a complex formed by combination of solvent moleculeswith molecules or ions of the solute. The solvent can be an organiccompound, an inorganic compound, or a mixture of both. Some examples ofsolvents include, but are not limited to, methanol,N,N-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water.

Unless indicated otherwise, the nomenclature of substituents that arenot explicitly defined herein are arrived at by naming the terminalportion of the functionality followed by the adjacent functionalitytoward the point of attachment. For example, the substituent“arylalkyloxycarbonyl” refers to the group (aryl)-(alkyl)-O—C(O)—.

It is understood that in all substituted groups defined above, polymersarrived at by defining substituents with further substituents tothemselves (e.g., substituted aryl having a substituted aryl group as asubstituent which is itself substituted with a substituted aryl group,which is further substituted by a substituted aryl group, etc.) are notintended for inclusion herein. In such cases, the maximum number of suchsubstitutions is three. For example, serial substitutions of substitutedaryl groups are limited to -substituted aryl-(substitutedaryl)-substituted aryl.

Similarly, it is understood that the above definitions are not intendedto include impermissible substitution patterns (e.g., methyl substitutedwith 5 fluoro groups). Such impermissible substitution patterns areeasily recognized by a person having ordinary skill in the art.

c. Compounds of the Invention

This invention provides novel 2,4-pyrimidinediamine compounds, prodrugsof the compounds, methods of making the compounds and methods of usingthese compounds in the treatment of conditions in which targeting of theJAK pathway or inhibition of JAK kinases, particularly JAK3, which aretherapeutically useful. These conditions include, but are not limitedto, debilitating and fatal diseases and disorders that affect bothchildren and adults, for example, oncological diseases, such asleukemia, including e.g., childhood leukemia, lymphoma, autoimmuneconditions, such as transplant rejection, and the other conditionsdescribed herein. Given the severity of and suffering caused by theseconditions, it is vital that new treatments are developed to treat theseconditions.

In one embodiment, the present invention provides a compound of formulaI, prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein:

-   -   ring A is aryl or heteroaryl;    -   p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3,        4, or 5 when ring A is bi- or tricyclic;    -   q is 0, 1, 2 or 3;    -   X is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino,        substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro,        alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,        cycloalkynyl and substituted cycloalkynyl;    -   Y is selected from the group consisting of hydrogen,        alk¹-SO₂N(R⁴)R⁵ and alk¹-N(R⁴)SO₂R⁵;    -   W is selected from the group consisting of alk²-SO₂N(R⁶)R⁷ and        alk²-N(R⁶)SO₂R⁷;    -   alk¹ and alk² are each independently a bond, straight or        branched chain C₁₋₆ alkylene group, cycloalkylene or substituted        cycloalkylene wherein:        -   if W is alk²-SO₂N(R⁶)R⁷ and alk² is a bond, then Y is            alk¹-N(R⁴)SO₂R⁵ and alk¹ is a bond;    -   R¹ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, alkenyl, substituted alkenyl, alkynyl,        substituted alkynyl, cycloalkyl and substituted cycloalkyl;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo, and oxo; or        -   R⁴ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A;    -   Z¹, Z², and Z³ each independently is carbon or nitrogen, wherein        no more than one of Z¹, Z², and Z³ is N; and        -   W is not attached to Z¹, Z² or Z³ when said Z¹, Z² or Z³ is            nitrogen;    -   each R³ independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        substituted alkynyl, cycloalkynyl, substituted cycloalkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo, oxo, and aminosulfonyl; or        -   R⁶ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to the ring containing Z¹, Z² and Z³; or        -   R⁷ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to the ring containing Z¹, Z² and Z³; or    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen        of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻; or        -   R⁴ and R⁵ together with the intervening atom or atoms bound            thereto form a heterocyclic or substituted heterocyclic            group; or    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or        -   R⁴ and R⁵ together with the intervening atom or atoms bound            thereto form a heterocyclic or a substituted heterocyclic            group;    -   R⁶ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, carboxyl, carboxyl        ester, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, acyl and M⁺, wherein M⁺ is a counterion selected        from the group consisting of K⁺, Na⁺, Li⁺ or ⁺N(R⁸)₄, wherein R⁸        is hydrogen or alkyl, and the nitrogen of —SO₂N(R⁶)R⁷ or        —N(R⁶)SO₂R⁷ is N⁻; or        -   R⁶ and R⁷ together with the intervening atom or atoms bound            thereto, form a heterocyclic or a substituted heterocyclic            group; or        -   if W is alk²-SO₂N(R⁶)R⁷, then R⁶ and R⁷ together with the            nitrogen atom bound thereto optionally form —N═C(OR⁹)₂            wherein each R⁹ independently is an alkyl group;    -   R⁷ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester,        and acyl;        provided:        when X is hydrogen, ring A is not benzimidazolyl or indazolyl;        and        when W is —CH₂SO₂N(R⁶)R⁷ and ring A is phenyl, then R² cannot be        a —NC(O)R¹⁰, —NC(S)R¹⁰, or —NSO₂R¹⁰ group, where R¹⁰ is an        alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclyl, substituted heterocyclyl, alkoxy, substituted        alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy,        heteroaryl or substituted heteroaryl.

Although M⁺ is preferably a monovalent cation it can also be a divalentcation with appropriate counterions, for example, two of the parent druganion, one of parent/one of other counter anion, etc.

In another embodiment, the present invention provides a compound offormula II, prodrugs, solvates, or pharmaceutically acceptable saltsthereof:

wherein:

-   -   ring A is aryl or heteroaryl;    -   p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3,        4, or 5 when ring A is bi- or tricyclic;    -   q is 0, 1, 2 or 3;    -   X is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino,        substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro,        alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,        cycloalkynyl, substituted cycloalkynyl;    -   Y is selected from the group consisting of hydrogen,        alk¹-SO₂N(R⁴)R⁵ and alk¹-N(R⁴)SO₂R⁵;    -   W is selected from the group consisting of alk²-SO₂N(R⁶)R⁷ and        alk²-N(R⁶)SO₂R⁷;    -   alk¹ and alk² are each independently a bond, straight or        branched chain C₁₋₆ alkylene group, cycloalkylene or substituted        cycloalkylene wherein:        -   if W is alk²-SO₂N(R⁶)R⁷ and alk² is a bond, then Y is            alk¹-N(R⁴)SO₂R⁵ and alk¹ is a bond;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo, and oxo; or        -   R⁴ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A;    -   each R³ independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        substituted alkynyl, cycloalkynyl, substituted cycloalkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo, and aminosulfonyl; or        -   R⁶ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic;            or        -   R⁷ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic;            or    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen        of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or        -   R⁴ and R⁵ together with the intervening atom or atoms bound            thereto form a heterocyclic or a substituted heterocyclic            group;    -   R⁶ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, carboxyl, carboxyl        ester, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, acyl and M⁺, wherein M⁺ is a counterion selected        from the group consisting of K⁺, Na⁺, Li⁺ or ⁺N(R⁸)₄, wherein R⁸        is hydrogen or alkyl, and the nitrogen of —SO₂N(R⁶)R⁷ or        —N(R⁶)SO₂R⁷ is N⁻; or        -   R⁶ and R⁷ together with the intervening atom or atoms bound            thereto, form a heterocyclic or a substituted heterocyclic            group; or        -   if W is alk²-SO₂N(R⁶)R⁷, then R⁶ and R⁷ together with the            nitrogen atom bound thereto optionally form —N═C(OR⁹)₂            wherein each R⁹ independently is an alkyl group;    -   R⁷ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester,        and acyl;        provided:        when X is hydrogen, ring A is not benzimidazolyl or indazolyl;        and        when W is —CH₂SO₂N(R⁶)R⁷ and ring A is phenyl, then R² cannot be        a —NC(O)R¹⁰, —NC(S)R¹⁰, or —NSO₂R¹⁰ group, where R¹⁰ is an        alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclyl, substituted heterocyclyl, alkoxy, substituted        alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy,        heteroaryl or substituted heteroaryl.

Although M⁺ is preferably a monovalent cation it can also be a divalentcation with appropriate counterions, for example, two of the parent druganion, one of parent/one of other counter anion, etc.

In another embodiment, the present invention provides a compound offormula III, prodrugs, solvates, or pharmaceutically acceptable saltsthereof:

wherein:

-   -   ring A is aryl or heteroaryl;    -   p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3,        4, or 5 when ring A is bi- or tricyclic;    -   q is 0, 1, 2 or 3;    -   X is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino,        substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro,        alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,        cycloalkynyl, substituted cycloalkynyl;    -   Y is selected from the group consisting of hydrogen,        alk¹-SO₂N(R⁴)R⁵ and alk¹-N(R⁴)SO₂R⁵;    -   alk¹ and alk² are each independently a bond or a straight or        branched chain C₁₋₆ alkylene group, wherein:        -   if alk² is a bond, then Y is alk¹-N(R⁴)SO₂R⁵ and alk¹ is a            bond;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        and halo; or        -   R⁴ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A;    -   each R³ independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        substituted alkynyl, cycloalkynyl, substituted cycloalkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo, and aminosulfonyl; or        -   R⁶ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic;            or        -   R⁷ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic;            or    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen        of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or        -   R⁴ and R⁵ together with the intervening atom or atoms bound            thereto form a heterocyclic or a substituted heterocyclic            group;    -   R⁶ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, carboxyl, carboxyl        ester, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, acyl and M⁺, wherein M⁺ is a counterion selected        from the group consisting of K⁺, Na⁺, Li⁺ or ⁺N(R⁸)₄, wherein R⁸        is hydrogen or alkyl, and the nitrogen of —SO₂N(R⁶)R⁷ or        —N(R⁶)SO₂R⁷ is N⁻; or        -   R⁶ and R⁷ together with the intervening atom or atoms bound            thereto, form a heterocyclic or a substituted heterocyclic            group; or    -   R⁷ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester,        and acyl;        provided:        when X is hydrogen, ring A is not benzimidazolyl or indazolyl;        and        when alk² is —CH₂ and ring A is phenyl, then R² cannot be a        —NC(O)R¹⁰, —NC(S)R¹⁰, or —NSO₂R¹⁰ group, where R¹⁰ is an alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclyl, substituted heterocyclyl, alkoxy, substituted        alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy,        heteroaryl or substituted heteroaryl.

In another embodiment, X is fluoro, alk² is —CH₂— and each of R⁶ and R⁷independently is hydrogen or alkyl. In yet another embodiment, ring A isphenyl, Y is hydrogen and p is 1 or 2. In yet another embodiment, eachR² independently is selected from the group consisting of alkyl,substituted alkyl, alkoxy, substituted alkoxy, halo and oxo halo andoxo;

-   -   wherein if R² is oxo, then the oxo substituent is attached to a        nonaromatic portion of ring A.

In another embodiment, X is fluoro, alk² is —CH₂— and each of R⁶ and R⁷independently is hydrogen or alkyl and ring A is a bicyclic heteroaryl.In yet another embodiment,

wherein R is hydrogen or methyl.

In another embodiment, X is fluoro, alk² is —CH₂— and each of R⁶ and R⁷independently is hydrogen or alkyl, ring A is a bicyclic heteroaryl andeach R² independently is selected from the group consisting of alkyl,substituted alkyl, aminoacyl, alkynyl and oxo;

-   -   wherein if R² is oxo, then the oxo substituent is attached to a        nonaromatic portion of ring A.

In another embodiment, X is fluoro, alk² is —CH₂— and each of R⁶ and R⁷independently is hydrogen or alkyl and Y is -alk¹-N(R⁴)SO₂R⁵. In yetanother embodiment, alk¹ is —CH₂— and each of R⁴ and R⁵ independently ishydrogen or alkyl.

In another embodiment, X is fluoro, alk² is —CH₂— and each of R⁶ and R⁷independently is hydrogen or alkyl and Y is -alk¹-SO₂N(R⁴)R⁵. In oneembodiment, alk¹ is a bond and each of R⁴ and R⁵ independently ishydrogen or alkyl. In another embodiment, alk¹ is —CH₂— and each of R⁴and R⁵ independently is selected from the group consisting of hydrogen,alkyl, substituted alkyl, cycloalkyl, heterocyclic and substitutedheterocyclic.

In another embodiment, this invention provides a compound selected fromthe group consisting of:

-   IV-5    N2-(3-Aminosulfonylmethylenephenyl)-5-fluoro-N4-[2-(2-N-morpholinoethylaminoacrbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine;-   IV-2    N2-[3-(Aminosulfonylmethylene)phenyl]-N4-[2,2-dimethyl-3-oxo-4-methyl-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;-   I-3    N2-(3-Aminosulfonylmethylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamine,-   I-14    N2-(3-Aminosulfonylmethylphenyl)-5-fluoro-N4-{4-[(prop-2-ynyloxy)carbonylaminomethyl]phenyl}-2,4-pyrimidinediamine;-   IV-3    N2-(3-Aminosulfonylmethylphenyl)-5-fluoro-N4-[1-(propyn-3-yl)indol-5-yl]-2,4-pyrimidinediamine;-   I-10    N4-(4-ethylsulfonylaminomethyl)phenyl-5-fluoro-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine;-   I-12    N4-(3-ethylsulfonylaminomethyl)phenyl-5-fluoro-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine;-   I-15    N4-[4-(2-ethylsulfonylamino)ethyl]phenyl-5-fluoro-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine;-   I-9    N4-[4-(N-ethylsulfonyl-N-propyl)aminomethyl]phenyl-5-fluoro-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine;-   I-8    N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine;-   I-2    N4-(4-ethylsulfonylaminomethyl)phenyl-5-methyl-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine;-   I-3    N2-[3-(Aminosulfonylmethylene)phenyl]-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;-   I-5    N2-[3-(Aminosulfonylmethylene)phenyl]-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine;-   I-13    N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-(4-tertiarybutylphenyl)-5-fluoro-2,4-pyrimidinediamine;-   I-1    N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-(4-cyanomethyleneoxyphenyl)-2,4-pyrimidinediamine;-   IV-4    N2-[3-(Aminosulfonylmethylene)phenyl]-N4-(3-cyanomethylene-1H-indol-5-yl)-5-fluoro-2,4-pyrimidinediamine;-   I-20    N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[(1-methylpyrazolyl-5-aminocarbonylmethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine;-   I-11    N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(N-methylaminosulfonylmethylene)phenyl]-2,4-pyrimidinediamine;-   I-7    N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(N,N-dimethylaminosulfonylmethylene)phenyl]-2,4-pyrimidinediamine;-   I-21    N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(1-methylpiperidin-4-ylaminosulfonylmethylene)phenyl]-2,4-pyrimidinediamine;-   I-16    N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[4-(N-methylaminosulfonylmethylene)phenyl]-2,4-pyrimidinediamine;-   I-18    N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(N-methylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;-   I-17    N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(N,N-dimethylaminosulfonyl)phenyl]-2,4-pyrimidinediamine;-   I-6    N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(N-cyclopropylaminosulfonylmethylene)phenyl]-2,4-pyrimidinediamine;-   IV-1    N2-[3-(Aminosulfonylmethylene)phenyl]-N4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine;    and-   I-19    N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(aminosulfonylmethylene)phenyl]-2,4-pyrimidinediamine.

In another embodiment, this invention provides a compound of formula IV,prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein:

-   -   ring A is aryl or heteroaryl;    -   p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3,        4, or 5 when ring A is bi- or tricyclic;    -   q is 0, 1, 2 or 3;    -   X is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino,        substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro,        alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,        cycloalkynyl and substituted cycloalkynyl;    -   Y is selected from the group consisting of hydrogen,        alk¹-SO₂N(R⁴)R⁵ and alk¹-N(R⁴)SO₂R⁵;    -   alk¹ and alk² are each independently a bond or a straight or        branched chain C₁₋₆ alkylene group;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo and oxo;        -   wherein if R² is oxo then the oxo substituent is attached to            a nonaromatic portion of ring A; or        -   R⁴ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A;    -   each R³ independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        substituted alkynyl, cycloalkynyl, substituted cycloalkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo, and aminosulfonyl; or        -   R⁶ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic;            or        -   R⁷ and one of R³, together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic;            or    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen        of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or        -   R⁴ and R⁵ together with the intervening atom or atoms bound            thereto form a heterocyclic or a substituted heterocyclic            group;    -   R⁶ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, carboxyl, carboxyl        ester, aryl, substituted aryl, heteroaryl, substituted        heteroaryl, acyl and M⁺, wherein M⁺ is a counterion selected        from the group consisting of K⁺, Na⁺, Li⁺ or ⁺N(R⁸)₄, wherein R⁸        is hydrogen or alkyl, and the nitrogen of —SO₂N(R⁶)R⁷ or        —N(R⁶)SO₂R⁷ is N⁻; or        -   R⁶ and R⁷ together with the intervening atom or atoms bound            thereto, form a heterocyclic or a substituted heterocyclic            group; or    -   R⁷ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester,        and acyl;        provided:        when X is hydrogen, ring A is not benzimidazolyl or indazolyl;        and        when alk² is —CH₂ and ring A is phenyl, then R² cannot be a        —NC(O)R¹⁰, —NC(S)R¹⁰, or —NSO₂R¹⁰ group, where R¹⁰ is an alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclyl, substituted heterocyclyl, alkoxy, substituted        alkoxy, aryl, substituted aryl, aryloxy, substituted aryloxy,        heteroaryl or substituted heteroaryl.

Although M⁺ is preferably a monovalent cation it can also be a divalentcation with appropriate counterions, for example, two of the parent druganion, one of parent/one of other counter anion, etc.

In one embodiment, Y is hydrogen or alk¹-N(R⁴)SO₂R⁵ and X is halo,methyl or trifluoromethyl. In yet another embodiment, X is fluoro. Inyet another embodiment, ring A is phenyl. In one embodiment, each ofalk¹ and alk² is —CH₂— or —CH₂CH₂— and each of R⁴, R⁵, R⁶ and R⁷independently is selected from the group consisting of hydrogen,cycloalkyl, and heteroaryl. In another embodiment, alk² is —CH₂— and R⁶and one of R³ together with the intervening atoms bound thereto, form aheterocyclic or substituted heterocyclic. In another embodiment, ring Ais a bicyclic heteroaryl, Y is hydrogen, and R⁴ and one of R², togetherwith the intervening atoms bound thereto, form a heterocyclic orsubstituted heterocyclic fused to ring A.

In one embodiment, this invention provides a compound of formula V,prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein:

-   -   ring A is aryl or heteroaryl;    -   p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3,        4, or 5 when ring A is bi- or tricyclic;    -   Y is selected from the group consisting of hydrogen,        alk¹-SO₂N(R⁴)R⁵ and alk¹-N(R⁴)SO₂R⁵;    -   alk¹ is a bond or a straight or branched chain C₁₋₆ alkylene        group;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo and oxo;        -   wherein if R² is oxo then the oxo substituent is attached to            a nonaromatic portion of ring A; or        -   R⁴ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A;    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen        of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or        -   R⁴ and R⁵ together with the intervening atom or atoms bound            thereto form a heterocyclic or a substituted heterocyclic            group; and    -   R⁷ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester,        acyl.

Although M⁺ is preferably a monovalent cation it can also be a divalentcation with appropriate counterions, for example, two of the parent druganion, one of parent/one of other counter anion, etc.

In another embodiment, this invention provides a compound of formula Vwherein the ring A is:

In another embodiment, this invention provides a compound selected fromthe group consisting of:

-   III-1    N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine,-   III-2    N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-[4-(cyclopropylsulfonylaminomethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine,-   III-3    N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine,-   III-4    N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(4-(prop-2-ynyloxy)phenyl)-5-fluoro-2,4-pyrimidinediamine;-   V-5    N2-(3-Benzyl-cyclopropanesulfonamide)-N4-(3,4-dihydroquinolin-1H-6-yl)-5-methyl-2,4-pyrimidinediamine;-   II-1    N2,N4-bis(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine,-   II-2    N2,N4-bis[442-cyclopropylsulfonylamino)ethyl]phenyl-5-methyl-2,4-pyrimidinediamine,-   II-3    N2,N4-bis[4-(pyrid-3-yl)sulfonylaminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine,    and-   II-4    N2,N4-bis(4-cyclopropylsulfonylaminomethyl)phenyl-5-trifluoromethyl-2,4-pyrimidinediamine.

In one embodiment, this invention provides a compound of formula VI,prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein:

-   -   p is 0, 1, 2 or 3;    -   q is 0, 1, 2 or 3;    -   X is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino,        substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro,        alkenyl, substituted alkenyl, alkynyl, substituted alkynyl,        cycloalkynyl and substituted cycloalkynyl;    -   each R² independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo and oxo;        -   wherein if R² is oxo then the oxo substituent is attached to            a nonaromatic portion of ring A; or    -   R⁴ and one of R² together with the intervening atoms bound        thereto form a heterocyclic or a substituted heterocyclic fused        to ring A; or        -   R⁵ and one of R² together with the intervening atoms bound            thereto form a heterocyclic or a substituted heterocyclic            fused to ring A;    -   each R³ independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl,        substituted alkynyl, cycloalkynyl, substituted cycloalkynyl,        alkynyloxy, amino, substituted amino, aryl, substituted aryl,        aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted        cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl,        substituted heteroaryl, heteroaryloxy, substituted        heteroaryloxy, heterocyclic, substituted heterocyclic,        heterocyclyloxy, substituted heterocyclyloxy, aminoacyl,        aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro,        halo, and aminosulfonyl;    -   R⁴ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a        counterion selected from the group consisting of K⁺, Na⁺, Li⁺        and N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen of        —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻;    -   R⁵ is selected from the group consisting of hydrogen, alkyl,        substituted alkyl, amino, cycloalkyl, substituted cycloalkyl,        heterocyclic, substituted heterocyclic, aryl, substituted aryl,        heteroaryl, substituted heteroaryl, and acyl; or        -   R⁴ and R⁵ together with the intervening atom or atoms bound            thereto form a heterocyclic or a substituted heterocyclic            group.

Although M⁺ is preferably a monovalent cation it can also be a divalentcation with appropriate counterions, for example, two of the parent druganion, one of parent/one of other counter anion, etc.

In one embodiment, R⁵ and one of R² together with the intervening atomsbound thereto form a heterocyclic or a substituted heterocyclic. In yetanother embodiment, X is halo and q is 0 or 1. In a preferredembodiment, X is fluoro.

In another embodiment, the invention provides a compound according toformula VII,

wherein each of R⁴ and R⁵ independently is hydrogen or alkyl, and X ishalo, methyl or trifluoromethyl.

In another embodiment, this invention provides a compound selected fromthe group consisting of:

-   VI-1:    (+/−)-N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;-   VI-2:    (+/−)-N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;-   VI-3:    (+/−)-N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[1-(cyclopropylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;-   VI-4:    (+/−)-N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[1-(cyclopropylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;-   VI-5:    (1R)-N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine;    and-   VI-6:    (1S)-N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine.

In another embodiment, this invention provides a compound of formulaVIII, prodrugs, solvates, or pharmaceutically acceptable salts thereof:

wherein:

-   -   q is 0, 1, 2 or 3; and    -   each R³ independently is selected from the group consisting of        alkyl, substituted alkyl, alkoxy, substituted alkoxy,        cycloalkyl, substituted cycloalkyl, halo, aminoacyl, nitrile,        aminosulfonyl, heterocyclic and substituted heterocyclic.

In another embodiment, this invention provides a compound selected fromthe group consisting of:

-   V-1    N2-(4-aminosulfonyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine;-   V-2    N2-(3-aminosulfonyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine;    and-   V-3    N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine.

In another embodiment, this invention providesN4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-N2-[3,3-dioxo-1H-benzo[e][1,3,4]oxathiazin-7-yl]-5-fluoro-2,4-pyrimidinediamine.

Those of skill in the art will appreciate that the 2,4-pyrimidinediaminecompounds described herein may include functional groups that can bemasked with progroups to create prodrugs. Such prodrugs are usually, butneed not be, pharmacologically inactive until converted into theiractive drug form. Indeed, many of the 2,4-pyrimidinediamine compoundsdescribed in this invention include promoieties that are hydrolyzable orotherwise cleavable under conditions of use. For example, ester groupscommonly undergo acid-catalyzed hydrolysis to yield the parentcarboxylic acid when exposed to the acidic conditions of the stomach, orbase-catalyzed hydrolysis when exposed to the basic conditions of theintestine or blood. Thus, when administered to a subject orally,2,4-pyrimidinediamine compounds that include ester moieties can beconsidered prodrugs of their corresponding carboxylic acid, regardlessof whether the ester form is pharmacologically active.

The mechanism by which the progroup(s) metabolizes is not critical, andcan be caused by, for example, hydrolysis under the acidic conditions ofthe stomach, as described above, and/or by enzymes present in thedigestive tract and/or tissues or organs of the body. Indeed, theprogroup(s) can be selected to metabolize at a particular site withinthe body. For example, many esters are cleaved under the acidicconditions found in the stomach. Prodrugs designed to cleave chemicallyin the stomach to the active 2,4-substituted pyrimidinediamine, canemploy progroups including such esters. Alternatively, the progroups canbe designed to metabolize in the presence of enzymes such as esterases,amidases, lipolases, phosphatases including ATPases and kinase etc.Progroups including linkages capable of metabolizing in vivo arewell-known, and include, by way of example and not limitation, ethers,thioethers, silylethers, silylthioethers, esters, thioesters,carbonates, thiocarbonates, carbamates, thiocarbamates, ureas,thioureas, carboxamides, etc. In some instances, a “precursor” groupthat is oxidized by oxidative enzymes such as, for example, cytochromeP450 of the liver, to a metabolizable group, can be selected.

In the prodrugs, any available functional moiety can be masked with aprogroup to yield a prodrug. Functional groups within the2,4-pyrimidinediamine compounds that can be masked with progroups forinclusion in a promoiety include, but are not limited to, amines(primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc.A wide variety of progroups, as well as the resultant promoieties,suitable for masking functional groups in active 2,4-pyrimidinediaminecompounds to yield prodrugs are well-known in the art. For example, ahydroxyl functional group can be masked as a sulfonate, ester orcarbonate promoiety, which can be hydrolyzed in vivo to provide thehydroxyl group. An amino functional group can be masked as an amide,carbamate, imine, urea, phosphenyl, phosphoryl or sulfenyl promoiety,which can be hydrolyzed in vivo to provide the amino group. A carboxylgroup can be masked as an ester (including silyl esters and thioesters),amide or hydrazide promoiety, which can be hydrolyzed in vivo to providethe carboxyl group. Other specific examples of suitable progroups andtheir respective promoieties will be apparent to those of skill in theart. All of these progroups, alone or in combinations, can be includedin the prodrugs.

In some embodiments of the 2,4-pyrimidinediamine compounds and methodsof using the compounds, the progroup(s) can be attached to any availableprimary or secondary amine, including, for example, the N2 nitrogen atomof the 2,4-pyrimidinediamine moiety, the N4 nitrogen atom of the2,4-pyrimidinediamine moiety, and/or a primary or secondary nitrogenatom included in a substituent on the 2,4-pyrimidinediamine compound.

In particular embodiments of the 2,4-pyrimidinediamine compounds andmethods of using the compounds, the prodrugs described herein are2,4-pyrimidinediamine compounds that are substituted at the N4 nitrogenof the 2,4-pyrimidinediamine moiety with a substituted or unsubstitutednitrogen-containing bicyclic ring that includes at least one progroup atone or more of: the nitrogen atom(s) of the bicyclic ring, the N2nitrogen of the 2,4-pyrimidinediamine moiety and/or the N4 nitrogen ofthe 2,4-pyrimidinediamine moiety.

As noted above, the identity of the progroup is not critical, providedthat it can be metabolized under the desired conditions of use, forexample under the acidic conditions found in the stomach and/or byenzymes found in vivo, to yield a the biologically active group, e.g.,the 2,4-substituted pyrimidinediamines as described herein. Thus,skilled artisans will appreciate that the progroup can comprisevirtually any known or later-discovered hydroxyl, amine or thiolprotecting group. Non-limiting examples of suitable protecting groupscan be found, for example, in Protective Groups in Organic Synthesis,Greene & Wuts, 2nd Ed., John Wiley & Sons, New York, 1991 (especiallypages 10-142 (alcohols, 277-308 (thiols) and 309-405 (amines) thedisclosure of which is incorporated herein by reference).

Additionally, the identity of the progroup(s) can also be selected so asto impart the prodrug with desirable characteristics. For example,lipophilic groups can be used to decrease water solubility andhydrophilic groups can be used to increase water solubility. In thisway, prodrugs specifically tailored for selected modes of administrationcan be obtained. The progroup can also be designed to impart the prodrugwith other properties, such as, for example, improved passive intestinalabsorption, improved transport-mediated intestinal absorption,protection against fast metabolism (slow-release prodrugs),tissue-selective delivery, passive enrichment in target tissues,targeting-specific transporters, etc. Groups capable of impartingprodrugs with these characteristics are well-known, and are described,for example, in Ettmayer et al., 2004, J. Med. Chem. 47(10):2393-2404,the disclosure of which is incorporated by reference. All of the variousgroups described in these references can be utilized in the prodrugsdescribed herein.

As noted above, progroup(s) may also be selected to increase the watersolubility of the prodrug as compared to the active drug. Thus theprogroup(s) may include or can be a group(s) suitable for imparting drugmolecules with improved water solubility. Such groups are well-known,and include, by way of example and not limitation, hydrophilic groupssuch as alkyl, aryl, arylalkyl, or cycloheteroalkyl groups substitutedwith one or more of an amine, alcohol, a carboxylic acid, a phosphorousacid, a sulfoxide, a sugar, an amino acid, a thiol, a polyol, an ether,a thioether and a quaternary amine salt.

The suitability of any particular progroup for a desired mode ofadministration can be confirmed in biochemical assays. For example, if aprodrug is to be administered by injection into a particular tissue ororgan, and the identities of the various enzyme(s) expressed in thetissue or organ are known, the particular prodrug can be tested formetabolism in biochemical assays with the isolated enzyme(s).Alternatively, the particular prodrug can be tested for metabolism tothe active 2,4-pyrimidinediamine compound with tissue and/or organextracts. Using tissue and/or organ extracts can be of particularconvenience when the identity(ies) of the enzymes expressed in thetarget tissues or organs are unknown, or in instances when the isolatedenzymes are not conveniently available. Skilled artisans will be able toreadily select progroups having metabolic properties (such as kinetics)suitable for particular applications using such in vitro tests. Ofcourse, specific prodrugs could also be tested for suitable metabolismin vitro animal models.

Numerous references teach the use and synthesis of prodrugs, including,for example, Ettmayer et al., ibid and Bungaard et al., (1989) J. Med.Chem. 32(12): 2503-2507. Additionally, the preparation and use ofprodrugs of 2,4-pyrimidinediamines is specifically taught in U.S.Provisional Patent Application 60/654,620, filed Feb. 18, 2005, entitled“Pyrimidinediamine Prodrugs and their Uses,” the disclosure of which ishereby incorporated by reference in its entirety.

One of ordinary skill in the art will appreciate that many of thecompounds and prodrugs thereof, as well as the various compound speciesspecifically described and/or illustrated herein, may exhibit thephenomena of tautomerism, conformational isomerism, geometric isomerismand/or optical isomerism. For example, the compounds and prodrugs of theinvention may include one or more chiral centers and/or double bonds andas a consequence may exist as stereoisomers, such as double-bond isomers(i.e., geometric isomers), enantiomers and diasteromers and mixturesthereof, such as racemic mixtures. As another example, the compounds andprodrugs of the invention may exist in several tautomeric forms,including the enol form, the keto form and mixtures thereof. As thevarious compound names, formulae and compound drawings within thespecification and claims can represent only one of the possibletautomeric, conformational isomeric, optical isomeric or geometricisomeric forms, it should be understood that the invention encompassesany tautomeric, conformational isomeric, optical isomeric and/orgeometric isomeric forms of the compounds or prodrugs having one or moreof the utilities described herein, as well as mixtures of these variousdifferent isomeric forms. In cases of limited rotation around the2,4-pryimidinediamine core structure, atropisomers are also possible andare also specifically included in the compounds of the invention. It isintended that the compounds encompassed herein are, with the exceptionof forms of isomerism, chemically stable and able to be isolated.

Depending upon the nature of the various substituents, the2,4-pyrimidinediamine compounds and prodrugs of the invention can be inthe form of salts. Such salts include salts suitable for pharmaceuticaluses (“pharmaceutically-acceptable salts”), salts suitable forveterinary uses, etc. Such salts can be derived from acids or bases, asis well-known in the art.

In one embodiment, the salt is a pharmaceutically acceptable salt.Generally, pharmaceutically acceptable salts are those salts that retainsubstantially one or more of the desired pharmacological activities ofthe parent compound and which are suitable for administration to humans.Pharmaceutically acceptable salts include acid addition salts formedwith inorganic acids or organic acids. Inorganic acids suitable forforming pharmaceutically acceptable acid addition salts include, by wayof example and not limitation, hydrohalide acids (e.g., hydrochloricacid, hydrobromic acid, hydroiodic acid, etc.), sulfuric acid, nitricacid, phosphoric acid, and the like. Organic acids suitable for formingpharmaceutically acceptable acid addition salts include, by way ofexample and not limitation, acetic acid, trifluoroacetic acid, propionicacid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, oxalicacid, pyruvic acid, lactic acid, malonic acid, succinic acid, malicacid, maleic acid, fumaric acid, tartaric acid, citric acid, palmiticacid, benzoic acid, 3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid,mandelic acid, alkylsulfonic acids (e.g., methanesulfonic acid,ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonicacid, etc.), arylsulfonic acids (e.g., benzenesulfonic acid,4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,4-toluenesulfonic acid, camphorsulfonic acid, etc.),4-methylbicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid,3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid,lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoicacid, salicylic acid, stearic acid, muconic acid, and the like.

Pharmaceutically acceptable salts also include salts formed when anacidic proton present in the parent compound is either replaced by ametal ion (e.g., an alkali metal ion, an alkaline earth metal ion or analuminum ion) or coordinates with an organic base (e.g., ethanolamine,diethanolamine, triethanolamine, N-methylglucamine, morpholine,piperidine, dimethylamine, diethylamine, triethylamine, ammonia, etc.).

The 2,4-pyrimidinediamine compounds and prodrugs thereof, as well as thesalts thereof, may also be in the form of hydrates, solvates andN-oxides, as are well-known in the art.

In another embodiment, this invention provides a compound, orstereoisomer, tautomer, prodrug, solvate, or pharmaceutically acceptablesalt thereof, selected from Tables I-VI.

TABLE I

# Y (R²)_(p) X CH₂SO₂N(R⁴)R⁵ I-1 H 4-OCH₂CN F 3-CH₂SO₂NH₂ I-24-(ETHYLSULFONAMIDOMETHYL)- P = 0 ME 4-CH₂SO₂NHME I-3 H 4-OCH₂C≡CH F3-CH₂SO₂NH₂ I-4 H 3-CL—4-OME F 3-CH₂SO₂NH₂ I-5 H 4-CL—3-OME F3-CH₂SO₂NH₂ I-6 3-(N- P = 0 F 3-CH₂SO₂NH₂ CYCLOPROPYLSULFAMOYLMETHYL)-I-7 3-(N,N- P = 0 F 3-CH₂SO₂NH₂ DIMETHYLSULFAMOYLMETHYL)- I-8 4- P = 0 F4-CH₂SO₂NHME (CYCLOPROPYLSULFONAMIDOMETHYL)- I-9 4-(N-(N-PROPYL)- P = 0F 4-CH₂SO₂NHME ETHYLSULFONAMIDOMETHYL)- I-10 4-(ETHYLSULFONAMIDOMETHYL)-P = 0 F 4-CH₂SO₂NHME I-11 4-(N-METHYLSULFAMOYLMETHYL)- P = 0 F3-CH₂SO₂NH₂ I-12 3-(N-ETHYLSULFONAMIDOMETHYL)- P = 0 F 4-CH₂SO₂NHME I-13H 4-^(T)BU F 3-CH₂SO₂NH₂ I-14 H 4-OCH₂C(O)OCH₂C≡CH F 3-CH₂SO₂NH₂ I-154-(ETHYLSULFONAMIDOETHYL)- P = 0 F 4-CH₂SO₂NHME I-164-(METHYLSULFAMOYLMETHYL)- P = 0 F 3-CH₂SO₂NH₂ I-173-(N,N-DIMETHYLSULFAMOYL)- P = 0 F 3-CH₂SO₂NH₂ I-183-(N-METHYLSULFAMOYL)- P = 0 F 3-CH₂SO₂NH₂ I-19 3-(SULFAMOYLMETHYL)- P =0 F 3-CH₂SO₂NH₂ I-20 H 4-((1-ME-PYRAZOL-3-YL)- F 3-CH₂SO₂NH₂ NHC(O)CH₂)—I-21 3-((1-ME-PIPERIDIN-4-YL)- P = 0 F 3-CH₂SO₂NH₂ SULFAMOYLMETHYL)-

TABLE II

# Y X W II-1 4-(CYCLOPROPYLSULFONAMIDOMETHYL)- ME —CH₂NHSO₂(CYCLOPROPYL)II-2 4-(CYCLOPROPYLSULFONAMIDOETHYL)- ME —CH₂CH₂NHSO₂(CYCLOPROPYL) II-34-((PYRIDIN-3-YL)-SULFONAMIDOMETHYL)- ME —CH₂NHSO₂(PYRIDIN-3-YL) II-44-(CYCLOPROPYLSULFONAMIDOMETHYL)- CF₃ —CH₂NHSO₂(CYCLOPROPYL)

TABLE III

        #

III-1

III-2

III-3

III-4

TABLE IV

        #

IV-1

IV-2

IV-3

IV-4

IV-5

TABLE V # STRUCTURE V-1

V-2

V-3

V-4

V-5

TABLE VI

# Q POSITION OF SO₂NH₂ VI-1 —NHSO₂METHYL 3 VI-2 —NHSO₂METHYL 4 VI-3—NHSO₂CYCLOPROPYL 3 VI-4 —NHSO₂CYCLOPROPYL 4 VI-5 (R)-NHSO₂METHYL 4 VI-6(S)-NHSO₂METHYL 4

d. Methods of the Invention

The present invention provides 2,4-pyrimidinediamine compounds andprodrugs thereof, as described herein, for use in therapy for theconditions as described herein. The present invention further providesuse of the compounds of the present invention in the manufacture of amedicament for the treatment of conditions in which targeting of the JAKpathway or inhibition of JAK kinases, particularly JAK3, can betherapeutically useful. These include conditions where the function oflymphocytes, macrophages, or mast cells is involved. Conditions in whichtargeting of the JAK pathway or inhibition of the JAK kinases,particularly JAK3 can be therapeutically useful include, leukemia,lymphoma, transplant rejection (e.g. pancreas islet transplantrejection), bone marrow transplant applications (e.g. graft-versus-hostdisease)), autoimmune diseases (e.g. rheumatoid arthritis, etc.),inflammation (e.g. asthma, etc.) and other conditions as described ingreater detail herein.

As noted previously, numerous conditions can be treated using the2,4-substituted pyrimidinediamine compounds, prodrugs thereof, andmethods of treatment as described herein. As used herein, “Treating” or“treatment” of a disease in a patient refers to (1) preventing thedisease from occurring in a patient that is predisposed or does not yetdisplay symptoms of the disease; (2) inhibiting the disease or arrestingits development; or (3) ameliorating or causing regression of thedisease. As well understood in the art, “treatment” is an approach forobtaining beneficial or desired results, including clinical results. Forthe purposes of this invention, beneficial or desired results caninclude one or more, but are not limited to, alleviation or ameliorationof one or more symptoms, diminishment of extent of a condition,including a disease, stabilized (i.e., not worsening) state of acondition, including diseases, preventing spread of disease, delay orslowing of condition, including disease, progression, amelioration orpalliation of the condition, including disease, state, and remission(whether partial or total), whether detectable or undetectable.Preferred are compounds that are potent and can be administered locallyat very low doses, thus minimizing systemic adverse effects.

The compounds described herein are potent and selective inhibitors ofJAK kinases, and particularly selective for cytokine signaling pathwayscontaining JAK3. As a consequence of this activity, the compounds can beused in a variety of in vitro, in vivo and ex vivo contexts to regulateor inhibit JAK kinase activity, signaling cascades in which JAK kinasesplay a role, and the biological responses effected by such signalingcascades. For example, in one embodiment, the compounds can be used toinhibit JAK kinase, either in vitro or in vivo, in virtually any celltype expressing the JAK kinase. For example, in hematopoietic cells, inwhich, for example JAK3 is predominantly expressed. They may also beused to regulate signal transduction cascades in which JAK kinases,particularly JAK3, play a role. Such JAK-dependent signal transductioncascades include, but are not limited to, the signaling cascades ofcytokine receptors that involve the common gamma chain, such as, forexample, the IL-4, IL-7, IL-5, IL-9, IL-15 and IL-21, or IL-2, IL-4,IL-7, IL-9, IL-15 and IL-21 receptor signaling cascades. The compoundsmay also be used in vitro or in vivo to regulate, and in particularinhibit, cellular or biological responses affected by such JAK-dependentsignal transduction cascades. Such cellular or biological responsesinclude, but are not limited to, IL-4/ramos CD23 upregulation, IL-2mediated T-cell proliferation, etc. Importantly, the compounds can beused to inhibit JAK kinases in vivo as a therapeutic approach towardsthe treatment or prevention of diseases mediated, either wholly or inpart, by a JAK kinase activity (referred to herein as “JAK kinasemediated diseases”). Non-limiting examples of JAK kinase mediateddiseases that can be treated or prevented with the compounds, include,but are not limited to allergies, asthma, autoimmune diseases such astransplant rejection (e.g., kidney, heart, lung, liver, pancreas, skin;host versus graft reaction (HVGR), graft versus host reaction (GVHR)etc.), rheumatoid arthritis, and amyotrophic lateral sclerosis, T-cellmediated autoimmune diseases such as multiple sclerosis, psoriasis andSjogren's syndrome, Type II inflammatory diseases such as vascularinflammation (including vasculitis, arteritis, atherosclerosis andcoronary artery disease), diseases of the central nervous system such asstroke, pulmonary diseases such as bronchitis obliteraus and primarypulmonary hypertension, and solid, delayed Type IV hypersensitivityreactions, and hematologic malignancies such as leukemia and lymphomas.

In another embodiment, this invention provides a method of inhibiting anactivity of a JAK kinase, comprising contacting the JAK kinase with anamount of a compound effective to inhibit an activity of the JAK kinasewherein the compound is selected from the compounds of this invention.In certain embodiments of the methods described herein, the method iscarried out in vivo. In certain embodiments of the methods describedherein, the method is carried out in vitro.

In certain embodiments of the methods, the compound is administered to asubject suffering from a T-cell mediated autoimmune disease. In someother embodiments, the subject is a transplant recipient suffering fromor predisposed to an allograft transplant rejection. In some otherembodiments, the compound is administered to a subject suffering from orpredisposed to develop a Type IV hypersensitivity reaction.

In another embodiment, this invention provides a method of inhibiting anactivity of a JAK kinase, comprising contacting in vitro a JAK3 kinasewith an amount of a compound effective to inhibit an activity of the JAKkinase wherein the compound is selected from the compounds of thisinvention.

In a specific embodiment, the compounds can be used to treat and/orprevent rejection in organ and/or tissue transplant recipients (i.e.,treat and/or prevent allorgraft rejection). Allografts can be rejectedthrough either a cell-mediated or humoral immune reaction of therecipient against transplant (histocompability) antigens present on themembranes of the donor's cells. The strongest antigens are governed by acomplex of genetic loci termed human leukocyte group A (HLA) antigens.Together with the ABO blood groups antigens, they are the chieftransplantation antigens detectable in humans.

Rejection following transplantation can generally be broken into threecategories: hyperacute, occurring hours to days followingtransplantation; acute, occurring days to months followingtransplantation; and chronic, occurring months to years followingtransplantation.

Hyperacute rejection is caused mainly by the production of hostantibodies that attack the graft tissue. In a hyperacute rejectionreaction, antibodies are observed in the transplant vascular very soonafter transplantation. Shortly thereafter, vascular clotting occurs,leading to ischemia, eventual necrosis and death. The graft infarctionis unresponsive to known immunosuppressive therapies. Because HLAantigens can be identified in vitro, pre-transplant screening is used tosignificantly reduce hyperacute rejection. As a consequence of thisscreening, hyperacute rejection is relative uncommon today.

Acute rejection is thought to be mediated by the accumulation of antigenspecific cells in the graft tissue. The T-cell-mediated immune reactionagainst these antigens (i.e., HVGR or GVHR) is the principle mechanismof acute rejection. Accumulation of these cells leads to damage of thegraft tissue. It is believed that both CD4+ helper T-cells and CD8+cytotoxic T-cells are involved in the process, and that the antigen ispresented by donor and host dendritic cells. The CD4+ helper T-cellshelp recruit other effector cells, such as macrophages and eosinophils,to the graft. Accessing T-cell activation signal transduction cascades(for example, CD28, CD40L and CD2 cascades) are also involved.

The cell-mediated acute rejection can be reversed in many cases byintensifying immunotherapy. After successful reversal, severely damagedelements of the graft heal by fibrosis and the remainder of the graftappears normal. After resolution of acute rejection, dosages ofimmunosuppressive drugs can be reduced to very low levels.

Chronic rejection, which is a particular problem in renal transplants,often progresses insidiously despite increased immunosuppressivetherapy. It is thought to be due, in large part, to cell-mediated TypeIV hypersensitivity. The pathologic profile differs from that of acuterejection. The arterial endothelium is primarily involved, withextensive proliferation that may gradually occlude the vessel lumen,leading to ischemia, fibrosis, a thickened intima and atheroscleroticchanges. Chronic rejection is mainly due to a progressive obliterationof graft vasculature, and resembles a slow, vasculitic process.

In Type IV hypersensitivity, CD8 cytotoxic T-cells and CD4 helper Tcells recognize either intracellular or extracellular synthesizedantigen when it is complexed, respectively, with either Class I or ClassII MHC molecules. Macrophages function as antigen-presenting cells andrelease IL-1, which promotes proliferation of helper T-cells. HelperT-cells release interferon gamma and IL-2, which together regulatedelayed hyperactivity reactions mediated by macrophage activation andimmunity mediated by T cells. In the case of organ transplant, thecytotoxic T-cells destroy the graft cells on contact.

Since JAK kinases play a critical role in the activation of T-cells, the2,4-pyrimidinediamine compounds described herein can be used to treatand/or prevent many aspects of transplant rejection, and areparticularly useful in the treatment and/or prevention of rejectionreactions that are mediated, at least in part, by T-cells, such as HVGRor GVHR. The 2,4-pyrimidinediamine compounds can also be used to treatand/or prevent chronic rejection in transplant recipients, and inparticular in renal transplant recipients.

In another embodiment, this invention provides a method of treating aT-cell mediated autoimmune disease, comprising administering to apatient suffering from such an autoimmune disease an amount of acompound effective to treat the autoimmune disease wherein the compoundis selected from the compounds of the invention. In certain embodimentsof the methods the autoimmune disease is multiple sclerosis (MS),psoriasis, or Sjogran's syndrome.

Therapy using the 2,4-pyrimidinediamine compounds described herein canbe applied alone, or it can be applied in combination with or adjunctiveto other common immunosuppressive therapies, such as, for example,mercaptopurine, corticosteroids such as prednisone, methylprednisoloneand prednisolone, alkylating agents such as cyclophosphamide,calcineurin inhibitors such as cyclosporine, sirolimus and tacrolimus,inhibitors of inosine monophosphate dehydrogenase (IMPDH) such asmycophenolate, mycophenolate mofetil and azathioprine, and agentsdesigned to suppress cellular immunity while leaving the recipient'shumoral immunologic response intact, including various antibodies (forexample, antilymphocyte globulin (ALG), antithymocyte globulin (ATG),monoclonal anti-T-cell antibodies (OKT3)) and irradiation. These variousagents can be used in accordance with their standard or common dosages,as specified in the prescribing information accompanying commerciallyavailable forms of the drugs (see also, the prescribing information inthe 2006 Edition of The Physician's Desk Reference), the disclosures ofwhich are incorporated herein by reference. Azathioprine is currentlyavailable from Salix Pharmaceuticals, Inc. under the brand name AZASAN;mercaptopurine is currently available from Gate Pharmaceuticals, Inc.under the brand name PURINETHOL; prednisone and prednisolone arecurrently available from Roxane Laboratories, Inc.; Methyl prednisoloneis currently available from Pfizer; sirolimus (rapamycin) is currentlyavailable from Wyeth-Ayerst under the brand name RAPAMUNE; tacrolimus iscurrently available from Fujisawa under the brand name PROGRAF;cyclosporine is current available from Novartis under the brand dameSANDIMMUNE and Abbott under the brand name GENGRAF; IMPDH inhibitorssuch as mycophenolate mofetil and mycophenolic acid are currentlyavailable from Roche under the brand name CELLCEPT and Novartis underthe brand name MYFORTIC; azathioprine is currently available from GlaxoSmith Kline under the brand name IMURAN; and antibodies are currentlyavailable from Ortho Biotech under the brand name ORTHOCLONE, Novartisunder the brand name SIMULECT (basiliximab) and Roche under the brandname ZENAPAX (daclizumab).

In another embodiment, the 2,4-pyrimidinediamine compounds could beadministered either in combination or adjunctively with an inhibitor ofa Syk kinase. Syk kinase is a tyrosine kinase known to play a criticalrole in Fcγ receptor signaling, as well as in other signaling cascades,such as those involving B-Cell receptor signaling (Tumer et al., (2000),Immunology Today 21:148-154) and integrins beta(1), beta (2) and beta(3) in neutrophils (Mocsavi et al., (2002), Immunity 16:547-558). Forexample, Syk kinase plays a pivotal role in high affinity IgE receptorsignaling in mast cells that leads to activation and subsequent releaseof multiple chemical mediators that trigger allergic attacks. However,unlike the JAK kinases, which help regulate the pathways involved indelayed, or cell-mediated Type IV hypersensitivity reactions, Syk kinasehelps regulate the pathways involved in immediate IgE-mediated, Type Ihypersensitivity reactions. Certain compounds that affect the Sykpathway may or may not also affect the JAK pathways.

Suitable Syk inhibitory compounds are described, for example, in Ser.No. 10/355,543 filed Jan. 31, 2003 (publication no. 2004/0029902); WO03/063794; Ser. No. 10/631,029 filed Jul. 29, 2003; WO 2004/014382; Ser.No. 10/903,263 filed Jul. 30, 2004; PCT/US2004/24716 filed Jul. 30, 2004(WO005/016893); Ser. No. 10/903,870 filed Jul. 30, 2004;PCT/US2004/24920 filed Jul. 30, 2004; Ser. No. 60/630,808 filed Nov. 24,2004; Ser. No. 60/645,424 filed Jan. 19, 2005; and Ser. No. 60/654,620,filed Feb. 18, 2005, the disclosures of which are incorporated herein byreference. The 2,4-pyrimidinediamine described herein and Syk inhibitorycompounds could be used alone, or in combination with one or moreconventional transplant rejection treatments, as described above.

In a specific embodiment, the 2,4-pyrimidinediamine compounds can beused to treat or prevent these diseases in patients that are eitherinitially non-responsive to (resistant), or that become non-responsiveto, treatment with a Syk inhibitory compound, or one of the othercurrent treatments for the particular disease. The 2,4-pyrimidinediaminecompounds could also be used in combination with Syk inhibitorycompounds in patients that are Syk-compound resistant or non-responsive.Suitable Syk-inhibitory compounds with which the 2,4-pyrimidinediaminecompounds can be administered are provided supra.

In another embodiment, this invention provides a method of treating aT-cell mediated autoimmune disease, comprising administering to apatient suffering from such an autoimmune disease an amount of acompound effective to treat the autoimmune disease wherein the compoundis selected from the compounds of the invention, as described herein andthe compound is administered in combination with, or adjunctively to, acompound that inhibits Syk kinase with an IC₅₀ in the range of at least10 μM.

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient,comprising administering to the transplant recipient an amount of acompound effective to treat or prevent the rejection wherein thecompound is selected from the compounds of the invention, as describedherein. In a further embodiment, the compound is administered to atissue or an organ prior to transplanting the tissue or organ in thetransplant recipient.

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the rejection is acute rejection, comprising administering to thetransplant recipient an amount of a compound effective to treat orprevent the rejection wherein the compound is selected from thecompounds of the invention.

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the rejection is chronic rejection, comprising administering tothe transplant recipient an amount of a compound effective to treat orprevent the rejection wherein the compound is selected from thecompounds of the invention.

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the rejection is mediated by HVGR or GVHR, comprisingadministering to the transplant recipient an amount of a compoundeffective to treat or prevent the rejection wherein the compound isselected from the compounds of this invention, as described herein.

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the allograft transplant is selected from a kidney, a heart, aliver and a lung, comprising administering to the transplant recipientan amount of a compound effective to treat or prevent the rejectionwherein the compound is selected from the compounds of this invention,as described herein.

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the allograft transplant is selected from a kidney, a heart, aliver and a lung, comprising administering to the transplant recipientan amount of a compound effective to treat or prevent the rejectionwherein the compound is selected from the compounds of the invention, asdescribed herein, in which the compound is administered in combinationwith, or adjunctively to, another immunosuppressant.

In another embodiment, this invention provides a method of treating orpreventing allograft transplant rejection in a transplant recipient, inwhich the allograft transplant is selected from a kidney, a heart, aliver and a lung, comprising administering to the transplant recipientan amount of a compound effective to treat or prevent the rejectionwherein the compound is selected from the compounds of the invention, asdescribed herein, in which the compound is administered in combinationwith, or adjunctively to, another immunosuppressant, in which theimmunosuppressant is selected from cyclosporine, tacrolimus, sirolimus,an inhibitor of IMPDH, mycophenolate, mycophanolate mofetil, ananti-T-Cell antibody and OKT3.

The 2,4-pyrimidinediamine compounds described herein are cytokinemoderators of IL-4 signaling. As a consequence, the2,4-pyrimidinediamine compounds could slow the response of Type Ihypersensitivity reactions. Thus, in a specific embodiment, the2,4-pyrimidinediamine compounds could be used to treat such reactions,and therefore the diseases associated with, mediated by or caused bysuch hypersensitivity reactions (for example, allergies),prophylactically. For example, an allergy sufferer could take one ormore of the JAK selective compounds described herein prior to expectedexposure to allergens to delay the onset or progress, or eliminatealtogether, an allergic response.

When used to treat or prevent such diseases, the 2,4-pyrimidinediaminecompounds can be administered singly, as mixtures of one or more2,4-pyrimidinediamine compounds or in mixture or combination with otheragents useful for treating such diseases and/or the symptoms associatedwith such diseases. The 2,4-pyrimidinediamine compounds may also beadministered in mixture or in combination with agents useful to treatother disorders or maladies, such as steroids, membrane stabilizers,5-lipoxygenase (5LO) inhibitors, leukotriene synthesis and receptorinhibitors, inhibitors of IgE isotype switching or IgE synthesis, IgGisotype switching or IgG synthesis, β-agonists, tryptase inhibitors,aspirin, cyclooxygenase (COX) inhibitors, methotrexate, anti-TNF drugs,retuxin, PD4 inhibitors, p38 inhibitors, PDE4 inhibitors, andantihistamines, to name a few. The 2,4-pyrimidinediamine compounds canbe administered per se in the form of prodrugs or as pharmaceuticalcompositions, comprising an active compound or prodrug.

In another embodiment, this invention provides a method of treating orpreventing a Type IV hypersensitivity reaction, comprising administeringto a subject an amount of a compound of effective to treat or preventthe hypersensitivity reaction wherein the compound is selected from thecompounds of this invention, as described herein.

In another embodiment, this invention provides a method of treating orpreventing a Type IV hypersensitivity reaction, which is practicalprophylactically, comprising administering to a subject an amount of acompound of effective to treat or prevent the hypersensitivity reactionwherein the compound is selected from the compounds of this invention,as described herein, and is administered prior to exposure to anallergen.

In another embodiment, this invention provides a method of inhibiting asignal transduction cascade in which JAK3 kinase plays a role,comprising contacting a cell expressing a receptor involved in such asignaling cascade with a compound wherein the compound is selected fromthe compounds of this invention, as described herein.

In another embodiment, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease wherein the compound is selected from thecompounds of this invention, as described herein.

In another embodiment, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, in which the JAK-mediateddisease is HVGR or GVHR, comprising administering to a subject an amountof compound effective to treat or prevent the JAK kinase-mediateddisease wherein the compound is selected from the compounds of theinvention, as described herein.

In another embodiment, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, in which the JAK-mediateddisease is acute allograft rejection, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease wherein the compound is selected from thecompounds of the invention, as described herein.

In another embodiment, this invention provides a method of treating orpreventing a JAK kinase-mediated disease, in which the JAK-mediateddisease is chronic allograft rejection, comprising administering to asubject an amount of compound effective to treat or prevent the JAKkinase-mediated disease wherein the compound is selected from thecompounds of the invention, as described herein.

Active compounds of the invention typically inhibit the JAK/Statpathway. The activity of a specified compound as an inhibitor of a JAKkinase can be assessed in vitro or in vivo. In some embodiments, theactivity of a specified compound can be tested in a cellular assay.Suitable assays include assays that determine inhibition of either thephosphorylation activity or ATPase activity of a JAK kinase. Thus, acompound is said to inhibit an activity of a JAK kinase if it inhibitsthe phosphorylation or ATPase activity of a JAK kinase with an IC₅₀ ofabout 20 μM or less.

One means of assaying for such inhibition is detection of the effect ofthe 2,4-pyrimidinediamine compounds on the upregulation of downstreamgene products. In the Ramos/IL4 assay, B-cells are stimulated with thecytokine Interleukin-4 (IL-4) leading to the activation of the JAK/Statpathway through phosphorylation of the JAK family kinases, JAK1 andJAK3, which in turn phosphorylate and activate the transcription factorStat-6. One of the genes upregulated by activated Stat-6 is the lowaffinity IgE receptor, CD23. To study the effect of inhibitors (e.g.,the 2,4-substituted pyrimindinediamine compounds described herein) onthe JAK1 and JAK3 kinases, human Ramos B cells are stimulated with humanIL-4. Twenty to 24 hours post stimulation, cells are stained forupregulation of CD23 and analyzed using flow cytometry (FACS). Areduction of the amount of CD23 present compared to control conditionsindicates the test compound actively inhibits the JAK kinase pathway. Anexemplary assay of this type is described in greater detail in Example2.

The activity of the active compounds of the invention may further becharacterized by assaying the effect of the 2,4-pyrimidinediaminecompounds described herein on the proliferative response of primaryhuman T-cells. In this assay, primary human T-cells derived fromperipheral blood and pre-activated through stimulation of the T-cellreceptor and CD28, proliferate in culture in response to the cytokineInterleukin-2 (IL-2). This proliferative response is dependent on theactivation of JAK1 and JAK3 tyrosine kinases, which phosphorylate andactivate the transcription factor Stat-5. The primary human T-cells areincubated with the 2,4-pyrimidinediamine compounds in the presence ofIL-2 for 72 hours and at the assay endpoint intracellular ATPconcentrations are measured to assess cell viability. A reduction incell proliferation compared to control conditions is indicative ofinhibition of the JAK kinase pathway. An exemplary assay of this type isdescribed in greater detail in Example 3.

The activity of the compounds of the invention may additionally becharacterized by assaying the effect of the 2,4-pyrimidinediaminecompounds described herein on A549 lung epithelial cells and U937 cells.A549 lung epithelial cells and U937 cells up-regulate ICAM-1 (CD54)surface expression in response to a variety of different stimuli.Therefore, using ICAM-1 expression as readout, test compound effects ondifferent signaling pathways can be assessed in the same cell type.Stimulation with IL-1β through the IL-1β receptor activates theTRAF6/NFκB pathway resulting in up-regulation of ICAM-1. IFNγ inducesICAM-1 up-regulation through activation of the JAK1/JAK2 pathway. Theup-regulation of ICAM-1 can be quantified by flow cytometry across acompound dose curve and EC₅₀ values are calculated. An exemplary assaysof this type are described in greater detail in Examples 4 and 5.

Active compounds as described herein generally inhibit the JAK kinasepathway with an IC₅₀ in the range of about 1 mM or less, as measured inthe assays described herein. Of course, skilled artisans will appreciatethat compounds which exhibit lower IC₅₀s, for example on the order of100 μM, 75 μM, 50 μM, 40 μM, 30 μM, 20 μM, 15 μM, 10 μM, 5 μM, 1 μM, 500nM, 100 nM, 10 nM, 1 nM, or even lower, can be particularly useful intherapeutic applications. In instances where activity specific to aparticular cell type is desired, the compound can be assayed foractivity with the desired cell type and counter-screened for a lack ofactivity against other cell types. The desired degree of “inactivity” insuch counter screens, or the desired ratio of activity vs. inactivitymay vary for different situations, and can be selected by the user.

The 2,4-pyrimidinediamine active compounds also typically inhibit IL-4stimulated expression of CD23 in B-cells with an IC₅₀ in the range ofabout 20 μM or less, typically in the range of about 10 μM, 1 μM, 500nM, 100 nM, 10 nM, 1 nM, or even lower. A suitable assay that can beused is the assay described in Example 2, “Assay for Ramos B-Cell LineStimulated with IL-4.” In certain embodiments, the active2,4-substituted pyrimidinediamine compounds have an IC₅₀ of less than orequal to 5 μM, greater than 5 μM but less than 20 μM, greater than 20μM, or greater than 20 μM but less than 50 μM in the assay described inExample 2.

Additionally, the 2,4-pyrimidinediamine active compounds also typicallyinhibit an activity of an human primary T-cells with an IC₅₀ in therange of about 20 μM or less, typically in the range of about 10 μM, 1μM, 500 nM, 100 nM, 10 nM, 1 nM, or even lower. The IC₅₀ against humanprimary T-cells can be determined in a standard in vitro assay withisolated human primary T-cells. A suitable assay that can be used is theassay described in Example 34, “Primary Human T-cell Proliferation AssayStimulated with IL-2.” In certain embodiments, the active2,4-substituted pyrimidinediamine compounds have an IC₅₀ of less than orequal to 5 μM, greater than 5 μM but less than 20 μM, greater than 20μM, or greater than 20 μM but less than 50 μM in the assay described inExample 3.

The 2,4-pyrimidinediamine active compounds also typically inhibitexpression of ICAM1 (CD54) induced by IFNγ exposure in U937 or A549cells with an IC₅₀ in the range of about 20 μM or less, typically in therange of about 10 μM, 500 nM, 100 nM, 10 nM, 1 nM, or even lower. TheIC₅₀ against expression of ICAM (CD54) in IFNγ stimulated cells can bedetermined in a functional cellular assay with an isolated A549 or U937cell line. Suitable assays that can be used are the assays described inExamples 4 and 5, “A549 Epithelial Line Stimulated with IFNγ,” or “U937IFNγ ICAM1 FACS Assay,” respectively. In certain embodiments, the active2,4-substituted pyrimidinediamine compounds have an IC₅₀ of less than orequal to 20 μM, greater than 20 μM, or greater than 20 μM but less than50 μM in the assays described in Example 4 or Example 5.

“Cell proliferative disorder” refers to a disorder characterized byabnormal proliferation of cells. A proliferative disorder does not implyany limitation with respect to the rate of cell growth, but merelyindicates loss of normal controls that affect growth and cell division.Thus, in some embodiments, cells of a proliferative disorder can havethe same cell division rates as normal cells but do not respond tosignals that limit such growth. Within the ambit of “cell proliferativedisorder” is neoplasm or tumor, which is an abnormal growth of tissue.Cancer refers to any of various malignant neoplasms characterized by theproliferation of cells that have the capability to invade surroundingtissue and/or metastasize to new colonization sites.

“Hematopoietic neoplasm” refers to a cell proliferative disorder arisingfrom cells of the hematopoietic lineage. Generally, hematopoiesis is thephysiological process whereby undifferentiated cells or stem cellsdevelop into various cells found in the peripheral blood. In the initialphase of development, hematopoietic stem cells, typically found in thebone marrow, undergo a series of cell divisions to form multipotentprogenitor cells that commit to two main developmental pathways: thelymphoid lineage and the myeloid lineage. The committed progenitor cellsof the myeloid lineage differentiate into three major sub-branchescomprised of the erythroid, megakaryocyte, and granulocyte/monocytedevelopmental pathways. An additional pathway leads to formation ofdendritic cells, which are involved in antigen presentation. Theerythroid lineage gives rise to red blood cells while the megakaryocyticlineage gives rise to blood platelets. Committed cells of thegranulocyte/monocyte lineage split into granulocyte or monocytedevelopmental pathways, the former pathway leading to formation ofneutrophils, eosinophils, and basophils and the latter pathway givingrise to blood monocytes and macrophages.

Committed progenitor cells of the lymphoid lineage develop into the Bcell pathway, T cell pathway, or the non-T/B cell pathway. Similar tothe myeloid lineage, an additional lymphoid pathway appears to give riseto dendritic cells involved in antigen presentation. The B cellprogenitor cell develops into a precursor B cell (pre-B), whichdifferentiates into B cells responsible for producing immunoglobulins.Progenitor cells of the T cell lineage differentiate into precursor Tcells (pre-T) that, based on the influence of certain cytokines, developinto cytotoxic or helper/suppressor T cells involved in cell mediatedimmunity. Non-T/B cell pathway leads to generation of natural killer(NK) cells. Neoplasms of hematopoietic cells can involve cells of anyphase of hematopoiesis, including hematopoietic stem cells, multipotentprogenitor cells, oligopotent committed progenitor cells, precursorcells, and mature differentiated cells. The categories of hematopoieticneoplasms can generally follow the descriptions and diagnostic criteriaemployed by those of skill in the art (see, e.g., InternationalClassification of Disease and Related Health Problems (ICD 10), WorldHealth Organization (2003)). Hematopoietic neoplasms can also becharacterized based on the molecular features, such as cell surfacemarkers and gene expression profiles, cell phenotype exhibited by theaberrant cells, and/or chromosomal aberrations (e.g., deletions,translocations, insertions, etc.) characteristic of certainhematopoietic neoplasms, such as the Philadelphia chromosome found inchronic myelogenous leukemia. Other classifications include NationalCancer Institute Working Formulation (Cancer, 1982, 49:2112-2135) andRevised European-American Lymphoma Classification (REAL).

“Lymphoid neoplasm” refers a proliferative disorder involving cells ofthe lymphoid lineage of hematopoiesis. Lymphoid neoplasms can arise fromhematopoietic stem cells as well as lymphoid committed progenitor cells,precursor cells, and terminally differentiated cells. These neoplasmscan be subdivided based on the phenotypic attributes of the aberrantcells or the differentiated state from which the abnormal cells arise.Subdivisions include, among others, B cell neoplasms, T cell neoplasms,NK cell neoplasms, and Hodgkin's lymphoma.

“Myeloid neoplasm” refers to proliferative disorder of cells of themyeloid lineage of hematopoiesis. Neoplasms can arise from hematopoieticstem cells, myeloid committed progenitor cells, precursor cells, andterminally differentiated cells. Myeloid neoplasms can be subdividedbased on the phenotypic attributes of the aberrant cells or thedifferentiated state from which the abnormal cells arise. Subdivisionsinclude, among others, myeloproliferative diseases,myelodysplastic/myeloproliferative diseases, myelodysplastic syndromes,acute myeloid leukemia, and acute biphenotypic leukemia.

Generally, cell proliferative disorders treatable with the compoundsdisclosed herein relate to any disorder characterized by aberrant cellproliferation. These include various tumors and cancers, benign ormalignant, metastatic or non-metastatic. Specific properties of cancers,such as tissue invasiveness or metastasis, can be targeted using themethods described herein. Cell proliferative disorders include a varietyof cancers, including, among others, breast cancer, ovarian cancer,renal cancer, gastrointestinal cancer, kidney cancer, bladder cancer,pancreatic cancer, lung squamous carcinoma, and adenocarcinoma.

Tumors that may be affected by certain drugs include tongue, mouth,pharynx, esophagus, stomach, small intestine, colon, rectum, anus,liver, gallbladder, pancreas, larynx, lung and bronchus, bones andjoints including synovial sarcoma and osteosarcoma, melanomas includingbasal cell carcinoma, squamous carcinoma, breast, cervix, endometrium,ovary, vulva, vagina, prostate, testis, penis, urinary bladder, kidneyand renal pelvis, ureter, eye, brain including glioma, glioblastoma,astrocytoma, neuroblastoma, medulloblastoma, and thyroid.

In some embodiments, the cell proliferative disorder treated is ahematopoietic neoplasm, which is aberrant growth of cells of thehematopoietic system. Hematopoietic malignancies can have its origins inpluripotent stem cells, multipotent progenitor cells, oligopotentcommitted progenitor cells, precursor cells, and terminallydifferentiated cells involved in hematopoiesis. Some hematologicalmalignancies are believed to arise from hematopoietic stem cells, whichhave the ability for self renewal. For instance, cells capable ofdeveloping specific subtypes of acute myeloid leukemia (AML) upontransplantation display the cell surface markers of hematopoietic stemcells, implicating hematopoietic stem cells as the source of leukemiccells. Blast cells that do not have a cell marker characteristic ofhematopoietic stem cells appear to be incapable of establishing tumorsupon transplantation (Blaire et al., 1997, Blood 89:3104-3112). The stemcell origin of certain hematological malignancies also finds support inthe observation that specific chromosomal abnormalities associated withparticular types of leukemia can be found in normal cells ofhematopoietic lineage as well as leukemic blast cells. For instance, thereciprocal translocation t(9q34;22q11) associated with approximately 95%of chronic myelogenous leukemia appears to be present in cells of themyeloid, erythroid, and lymphoid lineage, suggesting that thechromosomal aberration originates in hematopoietic stem cells. Asubgroup of cells in certain types of CML displays the cell markerphenotype of hematopoietic stem cells.

Although hematopoietic neoplasms often originate from stem cells,committed progenitor cells or more terminally differentiated cells of adevelopmental lineage can also be the source of some leukemias. Forexample, forced expression of the fusion protein Bcr/Abl (associatedwith chronic myelogenous leukemia) in common myeloid progenitor orgranulocyte/macrophage progenitor cells produces a leukemic-likecondition. Moreover, some chromosomal aberrations associated withsubtypes of leukemia are not found in the cell population with a markerphenotype of hematopoietic stem cells, but are found in a cellpopulation displaying markers of a more differentiated state of thehematopoietic pathway (Turhan et al., 1995, Blood 85:2154-2161). Thus,while committed progenitor cells and other differentiated cells may haveonly a limited potential for cell division, leukemic cells may haveacquired the ability to grow unregulated, in some instances mimickingthe self-renewal characteristics of hematopoietic stem cells (Passegueet al., Proc. Natl. Acad. Sci. USA, 2003, 100:11842-9).

In some embodiments, the hematopoietic neoplasm treated is a lymphoidneoplasm, where the abnormal cells are derived from and/or display thecharacteristic phenotype of cells of the lymphoid lineage. Lymphoidneoplasms can be subdivided into B-cell neoplasms, T and NK-cellneoplasms, and Hodgkin's lymphoma. B-cell neoplasms can be furthersubdivided into precursor B-cell neoplasm and mature/peripheral B-cellneoplasm. Exemplary B-cell neoplasms are precursor B-lymphoblasticleukemia/lymphoma (precursor B-cell acute lymphoblastic leukemia) whileexemplary mature/peripheral B-cell neoplasms are B-cell chroniclymphocytic leukemia/small lymphocytic lymphoma, B-cell prolymphocyticleukemia, lymphoplasmacytic lymphoma, splenic marginal zone B-celllymphoma, hairy cell leukemia, plasma cell myeloma/plasmacytoma,extranodal marginal zone B-cell lymphoma of MALT type, nodal marginalzone B-cell lymphoma, follicular lymphoma, mantle-cell lymphoma, diffuselarge B-cell lymphoma, mediastinal large B-cell lymphoma, primaryeffusion lymphoma, and Burkitt's lymphoma/Burkitt cell leukemia. T-celland Nk-cell neoplasms are further subdivided into precursor T-cellneoplasm and mature (peripheral) T-cell neoplasms. Exemplary precursorT-cell neoplasm is precursor T-lymphoblastic lymphoma/leukemia(precursor T-cell acute lymphoblastic leukemia) while exemplary mature(peripheral) T-cell neoplasms are T-cell prolymphocytic leukemia T-cellgranular lymphocytic leukemia, aggressive NK-cell leukemia, adult T-celllymphoma/leukemia (HTLV-1), extranodal NK/T-cell lymphoma, nasal type,enteropathy-type T-cell lymphoma, hepatosplenic gamma-delta T-celllymphoma, subcutaneous panniculitis-like T-cell lymphoma, Mycosisfungoides/Sezary syndrome, Anaplastic large-cell lymphoma, T/null cell,primary cutaneous type, Peripheral T-cell lymphoma, not otherwisecharacterized, Angioimmunoblastic T-cell lymphoma, Anaplastic large-celllymphoma, T/null cell, primary systemic type. The third member oflymphoid neoplasms is Hodgkin's lymphoma, also referred to as Hodgkin'sdisease. Exemplary diagnosis of this class that can be treated with thecompounds include, among others, nodular lymphocyte-predominantHodgkin's lymphoma, and various classical forms of Hodgkin's disease,exemplary members of which are Nodular sclerosis Hodgkin's lymphoma(grades 1 and 2), Lymphocyte-rich classical Hodgkin's lymphoma, Mixedcellularity Hodgkin's lymphoma, and Lymphocyte depletion Hodgkin'slymphoma. In various embodiments, any of the lymphoid neoplasms that areassociated with aberrant JAK activity can be treated with the JAKinhibitory compounds.

In some embodiments, the hematopoietic neoplasm treated is a myeloidneoplasm. This group comprises a large class of cell proliferativedisorders involving or displaying the characteristic phenotype of thecells of the myeloid lineage. Myeloid neoplasms can be subdivided intomyeloproliferative diseases, myelodysplastic/myeloproliferativediseases, myelodysplastic syndromes, and acute myeloid leukemias.Exemplary myeloproliferative diseases are chronic myelogenous leukemia(e.g., Philadelphia chromosome positive (t(9;22)(qq34;q11)), chronicneutrophilic leukemia, chronic eosinophilic leukemia/hypereosinophilicsyndrome, chronic idiopathic myelofibrosis, polycythemia vera, andessential thrombocythemia. Exemplary myelodysplastic/myeloproliferativediseases are chronic myelomonocytic leukemia, atypical chronicmyelogenous leukemia, and juvenile myelomonocytic leukemia. Exemplarymyelodysplastic syndromes are refractory anemia, with ringedsideroblasts and without ringed sideroblasts, refractory cytopenia(myelodysplastic syndrome) with multilineage dysplasia, refractoryanemia (myelodysplastic syndrome) with excess blasts, 5q-syndrome, andmyelodysplastic syndrome. In various embodiments, any of the myeloidneoplasms that are associated with aberrant JAK activity can be treatedwith the JAK inhibitory compounds.

In some embodiments, the JAK inhibitory compounds can be used to treatAcute myeloid leukemias (AML), which represent a large class of myeloidneoplasms having its own subdivision of disorders. These subdivisionsinclude, among others, AMLs with recurrent cytogenetic translocations,AML with multilineage dysplasia, and other AML not otherwisecategorized. Exemplary AMLs with recurrent cytogenetic translocationsinclude, among others, AML with t(8;21)(q22;q22), AML1(CBF-alpha)/ETO,Acute promyelocytic leukemia (AML with t(15;17)(q22;q11-12) andvariants, PML/RAR-alpha), AML with abnormal bone marrow eosinophils(inv(16)(p13q22) or t(16;16)(p13;q11), CBFb/MYH11X), and AML with 11q23(MLL) abnormalities. Exemplary AML with multilineage dysplasia are thosethat are associated with or without prior myelodysplastic syndrome.Other acute myeloid leukemias not classified within any definable groupinclude, AML minimally differentiated, AML without maturation, AML withmaturation, Acute myelomonocytic leukemia, Acute monocytic leukemia,Acute erythroid leukemia, Acute megakaryocytic leukemia, Acutebasophilic leukemia, and Acute panmyelosis with myelofibrosis.

e. Pharmaceutical Compositions of the Invention

Pharmaceutical compositions comprising the 2,4-pyrimidinediaminecompounds described herein (or prodrugs thereof) can be manufactured bymeans of conventional mixing, dissolving, granulating, dragee-makinglevigating, emulsifying, encapsulating, entrapping or lyophilizationprocesses. The compositions can be formulated in conventional mannerusing one or more physiologically acceptable carriers, diluents,excipients or auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically.

The 2,4-pyrimidinediamine compound or prodrug can be formulated in thepharmaceutical compositions per se, or in the form of a hydrate,solvate, N-oxide or pharmaceutically acceptable salt, as describedherein. Typically, such salts are more soluble in aqueous solutions thanthe corresponding free acids and bases, but salts having lowersolubility than the corresponding free acids and bases may also beformed.

In one embodiment, this invention provides a pharmaceutical formulationcomprising a compound selected from the compounds of the invention, asdescribed herein, or a prodrug thereof, and at least onepharmaceutically acceptable excipient, diluent, preservative, orstabilizer, or mixtures thereof.

In another embodiment, the methods can be practiced as a therapeuticapproach towards the treatment of the conditions described herein. Thus,in a specific embodiment, the 2,4-pyrimidinediamine compounds (and thevarious forms described herein, including pharmaceutical formulationscomprising the compounds (in the various forms)) can be used to treatthe conditions described herein in animal subjects, including humans.The methods generally comprise administering to the subject an amount ofa compound of the invention, or a salt, prodrug, hydrate or N-oxidethereof, effective to treat the condition. In one embodiment, thesubject is a mammal, including, but not limited to, bovine, horse,feline, canine, rodent, or primate. In another embodiment, the subjectis a human.

The compounds can be provided in a variety of formulations and dosages.The compounds can be provided in a pharmaceutically acceptable formincluding, where the compound or prodrug can be formulated in thepharmaceutical compositions per se, or in the form of a hydrate,solvate, N-oxide or pharmaceutically acceptable salt, as describedherein. Typically, such salts are more soluble in aqueous solutions thanthe corresponding free acids and bases, but salts having lowersolubility than the corresponding free acids and bases may also beformed. It is to be understood that reference to the compound,2,4-pyrimidinediamine compound, or “active” in discussions offormulations is also intended to include, where appropriate as known tothose of skill in the art, formulation of the prodrugs of the2,4-pyrimidinediamine compounds.

In one embodiment, the compounds are provided as non-toxicpharmaceutically acceptable salts, as noted previously. Suitablepharmaceutically acceptable salts of the compounds of this inventioninclude acid addition salts such as those formed with hydrochloric acid,fumaric acid, p-toluenesulphonic acid, maleic acid, succinic acid,acetic acid, citric acid, tartaric acid, carbonic acid or phosphoricacid. Salts of amine groups may also comprise quaternary ammonium saltsin which the amino nitrogen atom carries a suitable organic group suchas an alkyl, alkenyl, alkynyl or aralkyl moiety. Furthermore, where thecompounds of the invention carry an acidic moiety, suitablepharmaceutically acceptable salts thereof may include metal salts suchas alkali metal salts, e.g. sodium or potassium salts; and alkalineearth metal salts, e.g. calcium or magnesium salts.

The pharmaceutically acceptable salts of the present invention can beformed by conventional means, such as by reacting the free base form ofthe product with one or more equivalents of the appropriate acid in asolvent or medium in which the salt is insoluble, or in a solvent suchas water which is removed in vacuo or by freeze drying or by exchangingthe anions of an existing salt for another anion on a suitable ionexchange resin.

The present invention includes within its scope solvates of the2,4-pyrimidinediamine compounds and salts thereof, for example,hydrates.

The 2,4-pyrimidinediamine compounds may have one or more asymmetriccenters, and may accordingly exist both as enantiomers and asdiastereoisomers. It is to be understood that all such isomers andmixtures thereof are encompassed within the scope of the presentinvention.

The 2,4-pyrimidinediamine compounds can be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual,urethral (e.g., urethral suppository) or topical routes ofadministration (e.g., gel, ointment, cream, aerosol, etc.) and can beformulated, alone or together, in suitable dosage unit formulationscontaining conventional non-toxic pharmaceutically acceptable carriers,adjuvants, excipients and vehicles appropriate for each route ofadministration. In addition to the treatment of warm-blooded animalssuch as mice, rats, horses, cattle, sheep, dogs, cats, monkeys, etc.,the compounds of the invention can be effective in humans.

The pharmaceutical compositions for the administration of the2,4-pyrimidinediamine compounds may conveniently be presented in dosageunit form and can be prepared by any of the methods well known in theart of pharmacy. The pharmaceutical compositions can be, for example,prepared by uniformly and intimately bringing the active ingredient intoassociation with a liquid carrier or a finely divided solid carrier orboth, and then, if necessary, shaping the product into the desiredformulation. In the pharmaceutical composition the active objectcompound is included in an amount sufficient to produce the desiredtherapeutic effect. For example, pharmaceutical compositions of theinvention may take a form suitable for virtually any mode ofadministration, including, for example, topical, ocular, oral, buccal,systemic, nasal, injection, transdermal, rectal, vaginal, etc., or aform suitable for administration by inhalation or insufflation.

For topical administration, the JAK-selective compound(s) or prodrug(s)can be formulated as solutions, gels, ointments, creams, suspensions,etc. as are well-known in the art.

Systemic formulations include those designed for administration byinjection, e.g., subcutaneous, intravenous, intramuscular, intrathecalor intraperitoneal injection, as well as those designed for transdermal,transmucosal oral or pulmonary administration.

Useful injectable preparations include sterile suspensions, solutions oremulsions of the active compound(s) in aqueous or oily vehicles. Thecompositions may also contain formulating agents, such as suspending,stabilizing and/or dispersing agent. The formulations for injection canbe presented in unit dosage form, e.g., in ampules or in multidosecontainers, and may contain added preservatives.

Alternatively, the injectable formulation can be provided in powder formfor reconstitution with a suitable vehicle, including but not limited tosterile pyrogen free water, buffer, dextrose solution, etc., before use.To this end, the active compound(s) can be dried by any art-knowntechnique, such as lyophilization, and reconstituted prior to use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation. Such penetrants are knownin the art.

For oral administration, the pharmaceutical compositions may take theform of, for example, lozenges, tablets or capsules prepared byconventional means with pharmaceutically acceptable excipients such asbinding agents (e.g., pregelatinised maize starch, polyvinylpyrrolidoneor hydroxypropyl methylcellulose); fillers (e.g., lactose,microcrystalline cellulose or calcium hydrogen phosphate); lubricants(e.g., magnesium stearate, talc or silica); disintegrants (e.g., potatostarch or sodium starch glycolate); or wetting agents (e.g., sodiumlauryl sulfate). The tablets can be coated by methods well known in theart with, for example, sugars, films or enteric coatings. Additionally,the pharmaceutical compositions containing the 2,4-substitutedpyrimidinediamine as active ingredient or prodrug thereof in a formsuitable for oral use, may also include, for example, troches, lozenges,aqueous or oily suspensions, dispersible powders or granules, emulsions,hard or soft capsules, or syrups or elixirs. Compositions intended fororal use can be prepared according to any method known to the art forthe manufacture of pharmaceutical compositions and such compositions maycontain one or more agents selected from the group consisting ofsweetening agents, flavoring agents, coloring agents and preservingagents in order to provide pharmaceutically elegant and palatablepreparations. Tablets contain the active ingredient (including prodrug)in admixture with non-toxic pharmaceutically acceptable excipients whichare suitable for the manufacture of tablets. These excipients can be forexample, inert diluents, such as calcium carbonate, sodium carbonate,lactose, calcium phosphate or sodium phosphate; granulating anddisintegrating agents (e.g., corn starch, or alginic acid); bindingagents (e.g. starch, gelatin or acacia); and lubricating agents (e.g.magnesium stearate, stearic acid or talc). The tablets can be uncoatedor they can be coated by known techniques to delay disintegration andabsorption in the gastrointestinal tract and thereby provide a sustainedaction over a longer period. For example, a time delay material such asglyceryl monostearate or glyceryl distearate can be employed. They mayalso be coated by the techniques described in the U.S. Pat. Nos.4,256,108; 4,166,452; and 4,265,874 to form osmotic therapeutic tabletsfor control release. The pharmaceutical compositions of the inventionmay also be in the form of oil-in-water emulsions.

Liquid preparations for oral administration may take the form of, forexample, elixirs, solutions, syrups or suspensions, or they can bepresented as a dry product for constitution with water or other suitablevehicle before use. Such liquid preparations can be prepared byconventional means with pharmaceutically acceptable additives such assuspending agents (e.g., sorbitol syrup, cellulose derivatives orhydrogenated edible fats); emulsifying agents (e.g., lecithin oracacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethylalcohol, Cremophore™ or fractionated vegetable oils); and preservatives(e.g., methyl or propyl-p-hydroxybenzoates or sorbic acid). Thepreparations may also contain buffer salts, preservatives, flavoring,coloring and sweetening agents as appropriate.

Preparations for oral administration can be suitably formulated to givecontrolled release of the active compound or prodrug, as is well known.

For buccal administration, the compositions may take the form of tabletsor lozenges formulated in conventional manner.

For rectal and vaginal routes of administration, the active compound(s)can be formulated as solutions (for retention enemas) suppositories orointments containing conventional suppository bases such as cocoa butteror other glycerides.

For nasal administration or administration by inhalation orinsufflation, the active compound(s) or prodrug(s) can be convenientlydelivered in the form of an aerosol spray from pressurized packs or anebulizer with the use of a suitable propellant, e.g.,dichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, fluorocarbons, carbon dioxide or othersuitable gas. In the case of a pressurized aerosol, the dosage unit canbe determined by providing a valve to deliver a metered amount. Capsulesand cartridges for use in an inhaler or insufflator (for examplecapsules and cartridges comprised of gelatin) can be formulatedcontaining a powder mix of the compound and a suitable powder base suchas lactose or starch.

The pharmaceutical compositions can be in the form of a sterileinjectable aqueous or oleagenous suspension. This suspension can beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be a sterile injectablesolution or suspension in a non-toxic parenterally-acceptable diluent orsolvent. Among the acceptable vehicles and solvents that can be employedare water, Ringer's solution and isotonic sodium chloride solution. The2,4-pyrimidinediamine compounds may also be administered in the form ofsuppositories for rectal or urethral administration of the drug. Inparticular embodiments, the compounds can be formulated as urethralsuppositories, for example, for use in the treatment of fertilityconditions, particularly in males, e.g., for the treatment of testiculardysfunction.

According to the invention, 2,4-pyrimidinediamine compounds can be usedfor manufacturing a composition or medicament, including medicamentssuitable for rectal or urethral administration. The invention alsorelates to methods for manufacturing compositions including2,4-pyrimidinediamine compounds in a form that is suitable for urethralor rectal administration, including suppositories.

For topical use, creams, ointments, jellies, gels, solutions orsuspensions, etc., containing the 2,4-pyrimidinediamine compounds can beemployed. In certain embodiments, the 2,4-pyrimidinediamine compoundscan be formulated for topical administration with polyethylene glycol(PEG). These formulations may optionally comprise additionalpharmaceutically acceptable ingredients such as diluents, stabilizersand/or adjuvants. In particular embodiments, the topical formulationsare formulated for the treatment of allergic conditions and/or skinconditions including psoriasis, contact dermatitis and atopicdermatitis, among others described herein.

According to the invention, 2,4-pyrimidinediamine compounds can be usedfor manufacturing a composition or medicament, including medicamentssuitable for topical administration. The invention also relates tomethods for manufacturing compositions including 2,4-pyrimidinediaminecompounds in a form that is suitable for topical administration.

According to the present invention, 2,4-pyrimidinediamine compounds canalso be delivered by any of a variety of inhalation devices and methodsknown in the art, including, for example: U.S. Pat. No. 6,241,969; U.S.Pat. No. 6,060,069; U.S. Pat. No. 6,238,647; U.S. Pat. No. 6,335,316;U.S. Pat. No. 5,364,838; U.S. Pat. No. 5,672,581; WO96/32149;WO95/24183; U.S. Pat. No. 5,654,007; U.S. Pat. No. 5,404,871; U.S. Pat.No. 5,672,581; U.S. Pat. No. 5,743,250; U.S. Pat. No. 5,419,315; U.S.Pat. No. 5,558,085; WO98/33480; U.S. Pat. No. 5,364,833; U.S. Pat. No.5,320,094; U.S. Pat. No. 5,780,014; U.S. Pat. Nos. 5,658,878; 5,518,998;5,506,203; U.S. Pat. No. 5,661,130; U.S. Pat. No. 5,655,523; U.S. Pat.No. 5,645,051; U.S. Pat. No. 5,622,166; U.S. Pat. No. 5,577,497; U.S.Pat. No. 5,492,112; U.S. Pat. No. 5,327,883; U.S. Pat. No. 5,277,195;U.S. Pat. App. No. 20010041190; U.S. Pat. App. No. 20020006901; and U.S.Pat. App. No. 20020034477.

Included among the devices which can be used to administer particularexamples of the 2,4-pyrimidinediamine compounds are those well-known inthe art, such as, metered dose inhalers, liquid nebulizers, dry powderinhalers, sprayers, thermal vaporizers, and the like. Other suitabletechnology for administration of particular 2,4-pyrimidinediaminecompounds includes electrohydrodynamic aerosolizers.

In addition, the inhalation device is preferably practical, in the senseof being easy to use, small enough to carry conveniently, capable ofproviding multiple doses, and durable. Some specific examples ofcommercially available inhalation devices are Turbohaler (Astra,Wilmington, Del.), Rotahaler (Glaxo, Research Triangle Park, N.C.),Diskus (Glaxo, Research Triangle Park, N.C.), the Ultravent nebulizer(Mallinckrodt), the Acorn II nebulizer (Marquest Medical Products,Totowa, N.J.) the Ventolin metered dose inhaler (Glaxo, ResearchTriangle Park, N.C.), or the like. In one embodiment,2,4-pyrimidinediamine compounds can be delivered by a dry powder inhaleror a sprayer.

As those skilled in the art will recognize, the formulation of2,4-pyrimidinediamine compounds, the quantity of the formulationdelivered, and the duration of administration of a single dose depend onthe type of inhalation device employed as well as other factors. Forsome aerosol delivery systems, such as nebulizers, the frequency ofadministration and length of time for which the system is activated willdepend mainly on the concentration of 2,4-pyrimidinediamine compounds inthe aerosol. For example, shorter periods of administration can be usedat higher concentrations of 2,4-pyrimidinediamine compounds in thenebulizer solution. Devices such as metered dose inhalers can producehigher aerosol concentrations, and can be operated for shorter periodsto deliver the desired amount of 2,4-pyrimidinediamine compounds in someembodiments. Devices such as dry powder inhalers deliver active agentuntil a given charge of agent is expelled from the device. In this typeof inhaler, the amount of 2,4-pyrimidinediamine compounds in a givenquantity of the powder determines the dose delivered in a singleadministration. The formulation of 2,4-pyrimidinediamine is selected toyield the desired particle size in the chosen inhalation device.

Formulations of 2,4-pyrimidinediamine compounds for administration froma dry powder inhaler may typically include a finely divided dry powdercontaining 2,4-pyrimidinediamine compounds, but the powder can alsoinclude a bulking agent, buffer, carrier, excipient, another additive,or the like. Additives can be included in a dry powder formulation of2,4-pyrimidinediamine compounds, for example, to dilute the powder asrequired for delivery from the particular powder inhaler, to facilitateprocessing of the formulation, to provide advantageous powder propertiesto the formulation, to facilitate dispersion of the powder from theinhalation device, to stabilize to the formulation (e.g., antioxidantsor buffers), to provide taste to the formulation, or the like. Typicaladditives include mono-, di-, and polysaccharides; sugar alcohols andother polyols, such as, for example, lactose, glucose, raffinose,melezitose, lactitol, maltitol, trehalose, sucrose, mannitol, starch, orcombinations thereof; surfactants, such as sorbitols, diphosphatidylcholine, or lecithin; or the like.

The present invention also relates to a pharmaceutical compositionincluding 2,4-pyrimidinediamine compounds suitable for administration byinhalation. According to the invention, 2,4-pyrimidinediamine compoundscan be used for manufacturing a composition or medicament, includingmedicaments suitable for administration by inhalation. The inventionalso relates to methods for manufacturing compositions including2,4-pyrimidinediamine compounds in a form that is suitable foradministration, including administration by inhalation. For example, adry powder formulation can be manufactured in several ways, usingconventional techniques, such as described in any of the publicationsmentioned above and incorporated expressly herein by reference, and forexample, Baker, et al., U.S. Pat. No. 5,700,904, the entire disclosureof which is incorporated expressly herein by reference. Particles in thesize range appropriate for maximal deposition in the lower respiratorytract can be made by micronizing, milling, or the like. And a liquidformulation can be manufactured by dissolving the 2,4-pyrimidinediaminecompounds in a suitable solvent, such as water, at an appropriate pH,including buffers or other excipients.

Pharmaceutical compositions comprising the 2,4-pyrimidinediaminecompounds described herein (or prodrugs thereof) can be manufactured bymeans of conventional mixing, dissolving, granulating, dragee-makinglevigating, emulsifying, encapsulating, entrapping or lyophilizationprocesses. The compositions can be formulated in conventional mannerusing one or more physiologically acceptable carriers, diluents,excipients or auxiliaries which facilitate processing of the activecompounds into preparations which can be used pharmaceutically.

For ocular administration, the 2,4-pyrimidinediamine compound(s) orprodrug(s) can be formulated as a solution, emulsion, suspension, etc.suitable for administration to the eye. A variety of vehicles suitablefor administering compounds to the eye are known in the art. Specificnon-limiting examples are described in U.S. Pat. No. 6,261,547; U.S.Pat. No. 6,197,934; U.S. Pat. No. 6,056,950; U.S. Pat. No. 5,800,807;U.S. Pat. No. 5,776,445; U.S. Pat. No. 5,698,219; U.S. Pat. No.5,521,222; U.S. Pat. No. 5,403,841; U.S. Pat. No. 5,077,033; U.S. Pat.No. 4,882,150; and U.S. Pat. No. 4,738,851.

For prolonged delivery, the 2,4-pyrimidinediamine compound(s) orprodrug(s) can be formulated as a depot preparation for administrationby implantation or intramuscular injection. The active ingredient can beformulated with suitable polymeric or hydrophobic materials (e.g., as anemulsion in an acceptable oil) or ion exchange resins, or as sparinglysoluble derivatives, e.g., as a sparingly soluble salt. Alternatively,transdermal delivery systems manufactured as an adhesive disc or patchwhich slowly releases the active compound(s) for percutaneous absorptioncan be used. To this end, permeation enhancers can be used to facilitatetransdermal penetration of the active compound(s). Suitable transdermalpatches are described in for example, U.S. Pat. No. 5,407,713; U.S. Pat.No. 5,352,456; U.S. Pat. No. 5,332,213; U.S. Pat. No. 5,336,168; U.S.Pat. No. 5,290,561; U.S. Pat. No. 5,254,346; U.S. Pat. No. 5,164,189;U.S. Pat. No. 5,163,899; U.S. Pat. No. 5,088,977; U.S. Pat. No.5,087,240; U.S. Pat. No. 5,008,110; and U.S. Pat. No. 4,921,475.

Alternatively, other pharmaceutical delivery systems can be employed.Liposomes and emulsions are well-known examples of delivery vehiclesthat can be used to deliver active compound(s) or prodrug(s). Certainorganic solvents such as dimethylsulfoxide (DMSO) may also be employed,although usually at the cost of greater toxicity.

The pharmaceutical compositions may, if desired, be presented in a packor dispenser device which may contain one or more unit dosage formscontaining the active compound(s). The pack may, for example, comprisemetal or plastic foil, such as a blister pack. The pack or dispenserdevice can be accompanied by instructions for administration.

The 2,4-pyrimidinediamine compound(s) or prodrug(s) described herein, orcompositions thereof, will generally be used in an amount effective toachieve the intended result, for example in an amount effective to treator prevent the particular condition being treated. The compound(s) canbe administered therapeutically to achieve therapeutic benefit orprophylactically to achieve prophylactic benefit. By therapeutic benefitis meant eradication or amelioration of the underlying disorder beingtreated and/or eradication or amelioration of one or more of thesymptoms associated with the underlying disorder such that the patientreports an improvement in feeling or condition, notwithstanding that thepatient may still be afflicted with the underlying disorder. Forexample, administration of a compound to a patient suffering from anallergy provides therapeutic benefit not only when the underlyingallergic response is eradicated or ameliorated, but also when thepatient reports a decrease in the severity or duration of the symptomsassociated with the allergy following exposure to the allergen. Asanother example, therapeutic benefit in the context of asthma includesan improvement in respiration following the onset of an asthmaticattack, or a reduction in the frequency or severity of asthmaticepisodes. As another specific example, therapeutic benefit in thecontext of transplantation rejection includes the ability to alleviatean acute rejection episode, such as for example, HVGR or GVHR, or theability to prolong the time period between onset of acute rejectionepisodes and/or onset of chronic rejection. Therapeutic benefit alsoincludes halting or slowing the progression of the disease, regardlessof whether improvement is realized.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular condition being treated,the mode of administration, the severity of the condition being treatedand the age and weight of the patient, the bioavailability of theparticular active compound, etc. Determination of an effective dosage iswell within the capabilities of those skilled in the art.

As known by those of skill in the art, the preferred dosage of2,4-pyrimidinediamine compounds will also depend on the age, weight,general health and severity of the condition of the individual beingtreated. Dosage may also need to be tailored to the sex of theindividual and/or where administered by inhalation, the lung capacity ofthe individual. Dosage may also be tailored to individuals sufferingfrom more than one condition or those individuals who have additionalconditions which affect lung capacity and the ability to breathenormally, for example, emphysema, bronchitis, pneumonia, respiratoryinfections, etc. Dosage, and frequency of administration of thecompounds or prodrugs thereof, will also depend on whether the compoundsare formulated for treatment of acute episodes of a condition or for theprophylactic treatment of a disorder. For example, acute episodes ofallergic conditions, including allergy-related asthma, transplantrejection, etc. A skilled practitioner will be able to determine theoptimal dose for a particular individual.

For prophylactic administration, the compound can be administered to apatient at risk of developing one of the previously describedconditions. For example, if it is unknown whether a patient is allergicto a particular drug, the compound can be administered prior toadministration of the drug to avoid or ameliorate an allergic responseto the drug. Alternatively, prophylactic administration can be appliedto avoid the onset of symptoms in a patient diagnosed with theunderlying disorder. For example, a compound can be administered to anallergy sufferer prior to expected exposure to the allergen. Compoundsmay also be administered prophylactically to healthy individuals who arerepeatedly exposed to agents known to one of the above-describedmaladies to prevent the onset of the disorder. For example, a compoundcan be administered to a healthy individual who is repeatedly exposed toan allergen known to induce allergies, such as latex, in an effort toprevent the individual from developing an allergy. Alternatively, acompound can be administered to a patient suffering from asthma prior topartaking in activities which trigger asthma attacks to lessen theseverity of, or avoid altogether, an asthmatic episode.

In the context of transplant rejection, the compound can be administeredwhile the patient is not having an acute rejection reaction to avoid theonset of rejection and/or prior to the appearance of clinicalindications of chronic rejection. The compound can be administeredsystemically to the patient as well as administered to the tissue ororgan prior to transplanting the tissue or organ in the patient.

The amount of compound administered will depend upon a variety offactors, including, for example, the particular indication beingtreated, the mode of administration, whether the desired benefit isprophylactic or therapeutic, the severity of the indication beingtreated and the age and weight of the patient, the bioavailability ofthe particular active compound, etc. Determination of an effectivedosage is well within the capabilities of those skilled in the art.

Effective dosages can be estimated initially from in vitro assays. Forexample, an initial dosage for use in animals can be formulated toachieve a circulating blood or serum concentration of active compoundthat is at or above an IC₅₀ of the particular compound as measured in asin vitro assay. Calculating dosages to achieve such circulating blood orserum concentrations taking into account the bioavailability of theparticular compound is well within the capabilities of skilled artisans.For guidance, the reader is referred to Fingl & Woodbury, “GeneralPrinciples,” In: Goodman and Gilman's The Pharmaceutical Basis ofTherapeutics, Chapter 1, pp. 1-46, latest edition, Permagon Press, andthe references cited therein.

Initial dosages can also be estimated from in vivo data, such as animalmodels. Animal models useful for testing the efficacy of compounds totreat or prevent the various diseases described above are well-known inthe art. Suitable animal models of hypersensitivity or allergicreactions are described in Foster, (1995) Allergy 50(21Suppl):6-9,discussion 34-38 and Tumas et al., (2001), J. Allergy Clin. Immunol.107(6): 1025-1033. Suitable animal models of allergic rhinitis aredescribed in Szelenyi et al., (2000), Arzneimittelforschung50(11):1037-42; Kawaguchi et al., (1994), Clin. Exp. Allergy24(3):238-244 and Sugimoto et al., (2000), Immunopharmacology 48(1):1-7.Suitable animal models of allergic conjunctivitis are described inCarreras et al., (1993), Br. J. Ophthalmol. 77(8):509-514; Saiga et al.,(1992), Ophthalmic Res. 24(1):45-50; and Kunert et al., (2001), Invest.Ophthalmol. Vis. Sci. 42(11):2483-2489. Suitable animal models ofsystemic mastocytosis are described in O'Keefe et al., (1987), J. Vet.Intern. Med. 1(2):75-80 and Bean-Knudsen et al., (1989), Vet. Pathol.26(1):90-92. Suitable animal models of hyper IgE syndrome are describedin Claman et al., (1990), Clin. Immunol. Immunopathol. 56(1):46-53.Suitable animal models of B-cell lymphoma are described in Hough et al.,(1998), Proc. Natl. Acad. Sci. USA 95:13853-13858 and Hakim et al.,(1996), J. Immunol. 157(12):5503-5511. Suitable animal models of atopicdisorders such as atopic dermatitis, atopic eczema and atopic asthma aredescribed in Chan et al., (2001), J. Invest. Dermatol. 117(4):977-983and Suto et al., (1999), Int. Arch. Allergy Immunol. 120(Suppl 1):70-75.Suitable animal models of transplant rejection, such as models of HVGRare described in O'Shea et al., (2004), Nature Reviews Drug Discovery3:555-564; Cetkovic-Curlje & Tibbles, (2004), Current PharmaceuticalDesign 10:1767-1784; and Chengelian et al., (2003), Science 302:875-878.Ordinarily skilled artisans can routinely adapt such information todetermine dosages suitable for human administration.

Dosage amounts will typically be in the range of from about 0.0001 or0.001 or 0.01 mg/kg/day to about 100 mg/kg/day, but can be higher orlower, depending upon, among other factors, the activity of thecompound, its bioavailability, the mode of administration and variousfactors discussed above. Dosage amount and interval can be adjustedindividually to provide plasma levels of the compound(s) which aresufficient to maintain therapeutic or prophylactic effect. For example,the compounds can be administered once per week, several times per week(e.g., every other day), once per day or multiple times per day,depending upon, among other things, the mode of administration, thespecific indication being treated and the judgment of the prescribingphysician. In cases of local administration or selective uptake, such aslocal topical administration, the effective local concentration ofactive compound(s) may not be related to plasma concentration. Skilledartisans will be able to optimize effective local dosages without undueexperimentation.

Preferably, the compound(s) will provide therapeutic or prophylacticbenefit without causing substantial toxicity. Toxicity of thecompound(s) can be determined using standard pharmaceutical procedures.The dose ratio between toxic and therapeutic (or prophylactic) effect isthe therapeutic index. Compounds(s) that exhibit high therapeuticindices are preferred.

The foregoing disclosure pertaining to the dosage requirements for the2,4-substituted pyrimidinediamine compounds is pertinent to dosagesrequired for prodrugs, with the realization, apparent to the skilledartisan, that the amount of prodrug(s) administered will also dependupon a variety of factors, including, for example, the bioavailabilityof the particular prodrug(s) the conversation rate and efficiency intoactive drug compound under the selected route of administration, etc.Determination of an effective dosage of prodrug(s) for a particular useand mode of administration is well within the capabilities of thoseskilled in the art.

Effective dosages can be estimated initially from in vitro activity andmetabolism assays. For example, an initial dosage of prodrug for use inanimals can be formulated to achieve a circulating blood or serumconcentration of the metabolite active compound that is at or above anIC₅₀ of the particular compound as measured in as in vitro assay, suchas the in vitro CHMC or BMMC and other in vitro assays described in U.S.application Ser. No. 10/355,543 filed Jan. 31, 2003 (US2004/0029902A1),international application Serial No. PCT/US03/03022 filed Jan. 31, 2003(WO 03/063794), U.S. application Ser. No. 10/631,029 filed Jul. 29,2003, international application Serial No. PCT/US03/24087(WO2004/014382), U.S. application Ser. No. 10/903,263 filed Jul. 30,2004, and international application Serial No. PCT/US2004/24716(WO005/016893). Calculating dosages to achieve such circulating blood orserum concentrations taking into account the bioavailability of theparticular prodrug via the desired route of administration is wellwithin the capabilities of skilled artisans. For guidance, the reader isreferred to Fingi & Woodbury, “General Principles,” In: Goodman andGilman's The Pharmaceutical Basis of Therapeutics, Chapter 1, pp. 1-46,latest edition, Permagon Press, and the references cited therein.

Also provided are kits for administration of the 2,4-substitutedpyrimidinediamine, prodrug thereof or pharmaceutical formulationscomprising the compound, that may include a dosage amount of at leastone 2,4-pyrimidinediamine or a composition comprising at least one2,4-pyrimidinediamine as disclosed herein. Kits may further comprisesuitable packaging and/or instructions for use of the compound. Kits mayalso comprise a means for the delivery of the at least one2,4-pyrimidinediamine or compositions comprising at least one2,4-substituted pyrimidinediamine, such as an inhaler, spray dispenser(e.g. nasal spray), syringe for injection or pressure pack for capsules,tables, suppositories, or other device as described herein.

Additionally, the compounds of the present invention can be assembled inthe form of kits. The kit provides the compound and reagents to preparea composition for administration. The composition can be in a dry orlyophilized form, or in a solution, particularly a sterile solution.When the composition is in a dry form, the reagent may comprise apharmaceutically acceptable diluent for preparing a liquid formulation.The kit may contain a device for administration or for dispensing thecompositions, including, but not limited to syringe, pipette,transdermal patch, or inhalant.

The kits may include other therapeutic compounds for use in conjunctionwith the compounds described herein. In one embodiment, the therapeuticagents are immunosuppressant or anti-allergan compounds. These compoundscan be provided in a separate form, or mixed with the compounds of thepresent invention.

The kits will include appropriate instructions for preparation andadministration of the composition, side effects of the compositions, andany other relevant information. The instructions can be in any suitableformat, including, but not limited to, printed matter, videotape,computer readable disk, or optical disc.

In one embodiment, this invention provides a kit comprising a compoundselected from the compounds of the invention, as described herein, or aprodrug thereof, packaging and instructions for use.

In another embodiment, this invention provides a kit comprising thepharmaceutical formulation comprising a compound selected from thecompounds of the invention, as described herein, or a prodrug thereof,and at least one pharmaceutically acceptable excipient, diluent,preservative, or stabilizer, or mixtures thereof, packaging, andinstructions for use.

In another aspect of the invention, kits for treating an individual whosuffers from or is susceptible to the conditions described herein areprovided, comprising a container comprising a dosage amount of an2,4-pyrimidinediamine or composition as disclosed herein, andinstructions for use. The container can be any of those known in the artand appropriate for storage and delivery of oral, intravenous, topical,rectal, urethral, or inhaled formulations.

Kits may also be provided that contain sufficient dosages of the2,4-pyrimidinediamine or composition to provide effective treatment foran individual for an extended period, such as a week, 2 weeks, 3, weeks,4 weeks, 6 weeks or 8 weeks or more.

f. General Synthesis of the Compounds of the Invention

The 2,4-pyrimidinediamine compounds and prodrugs of the invention can besynthesized via a variety of different synthetic routes usingcommercially available starting materials and/or starting materialsprepared by conventional synthetic methods. Suitable exemplary methodsthat can be routinely adapted to synthesize the 2,4-pyrimidinediaminecompounds and prodrugs of the invention are found in U.S. Pat. No.5,958,935, the disclosure of which is incorporated herein by reference.Specific examples describing the synthesis of numerous2,4-pyrimidinediamine compounds and prodrugs, as well as intermediatestherefore, are described in copending U.S. application Ser. No.10/355,543, filed Jan. 31, 2003 (US2004/0029902A1), the contents ofwhich are incorporated herein by reference. Suitable exemplary methodsthat can be routinely used and/or adapted to synthesize active2,4-pyrimidinediamine compounds can also be found in internationalapplication Serial No. PCT/US03/03022 filed Jan. 31, 2003 (WO03/063794), U.S. application Ser. No. 10/631,029 filed Jul. 29, 2003,international application Serial No. PCT/US03/24087 (WO2004/014382),U.S. application Ser. No. 10/903,263 filed Jul. 30, 2004, andinternational application Serial No. PCT/US2004/24716 (WO005/016893),the disclosures of which are incorporated herein by reference. All ofthe compounds described herein (including prodrugs) can be prepared byroutine adaptation of these methods.

Exemplary synthetic methods for the 2,4-substituted pyrimidinediaminesdescribed herein are described below. Those of skill in the art willalso be able to readily adapt these methods for the synthesis ofspecific 2,4-substituted pyrimidinediamines as described herein.

A variety of exemplary synthetic routes that can be used to synthesizethe 2,4-pyrimidinediamine compounds of the invention are described inSchemes (I)-(VII), below. These methods can be routinely adapted tosynthesize the 2,4-pyrimidinediamine compounds and prodrugs describedherein.

In one exemplary embodiment, the compounds can be synthesized fromsubstituted or unsubstituted uracils as illustrated in Scheme (I),below:

In Scheme (I), ring A, R¹, (R²)_(p), (R³)_(q), X, W, Y, Z¹, Z² and Z³are as defined herein. According to Scheme (I), uracil A-1 isdihalogenated at the 2- and 4-positions using a standard halogenatingagent such as POCl₃ (or other standard halogenating agent) understandard conditions to yield 2,4-dichloropyrimidine A-2. Depending uponthe X substituent, in pyrimidinediamine A-2, the chloride at the C4position is more reactive towards nucleophiles than the chloride at theC2 position. This differential reactivity can be exploited to synthesize2,4-pyrimidinediamines A-7 by first reacting 2,4-dichloropyrimidine A-2with one equivalent of amine A-3, yielding4N-substituted-2-chloro-4-pyrimidineamine A-4, followed by amine A-5 toyield a 2,4-pyrimidinediamine derivative A-6, where N4 nitrogen can beselectively alkylated to give compounds of formula I.

Typically, the C4 halide is more reactive towards nucleophiles, asillustrated in the Scheme. However, as will be recognized by skilledartisans, the identity of the X substituent may alter this reactivity.For example, when X is trifluoromethyl, a 50:50 mixture of4N-substituted-4-pyrimidineamine A-4 and the corresponding2N-substituted-2-pyrimidineamine is obtained. The regioselectivity ofthe reaction can also be controlled by adjusting the solvent and othersynthetic conditions (such as temperature), as is well-known in the art.

The reactions depicted in Scheme (I) may proceed more quickly when thereaction mixtures are heated via microwave. When heating in thisfashion, the following conditions can be used: heat to 175° C. inethanol for 5-20 min. in a Smith Reactor (Personal Chemistry, Uppsala,Sweden) in a sealed tube (at 20 bar pressure).

The uracil A-1 starting materials can be purchased from commercialsources or prepared using standard techniques of organic chemistry.Commercially available uracils that can be used as starting materials inScheme (I) include, by way of example and not limitation, uracil(Aldrich #13,078-8; CAS Registry 66-22-8); 5-bromouracil (Aldrich #85,247-3; CAS Registry 51-20-7; 5-fluorouracil (Aldrich #85, 847-1; CASRegistry 51-21-8); 5-iodouracil (Aldrich #85, 785-8; CAS Registry696-07-1); 5-nitrouracil (Aldrich #85, 276-7; CAS Registry 611-08-5);5-(trifluoromethyl)-uracil (Aldrich #22, 327-1; CAS Registry 54-20-6).Additional 5-substituted uracils are available from GeneralIntermediates of Canada, Inc., Edmonton, Calif. and/or Interchim, Cedex,France, or can be prepared using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

Amines A-3 and A-5 can be purchased from commercial sources or,alternatively, can be synthesized utilizing standard techniques. Forexample, suitable amines can be synthesized from nitro precursors usingstandard chemistry. Specific exemplary reactions are provided in theExamples section. See also Vogel, 1989, Practical Organic Chemistry,Addison Wesley Longman, Ltd. and John Wiley & Sons, Inc.

Skilled artisans will recognize that in some instances, amines A-3 andA-5 and/or substituent X on uracil A-1 may include functional groupsthat require protection during synthesis. The exact identity of anyprotecting group(s) used will depend upon the identity of the functionalgroup being protected, and will be apparent to those of skill in theart. Guidance for selecting appropriate protecting groups, as well assynthetic strategies for their attachment and removal, can be found, forexample, in Greene & Wuts, Protective Groups in Organic Synthesis, 3dEdition, John Wiley & Sons, Inc., New York (1999) and the referencescited therein (hereinafter “Greene & Wuts”).

Thus, protecting group refers to a group of atoms that, when attached toa reactive functional group in a molecule, mask, reduce or prevent thereactivity of the functional group. Typically, a protecting group can beselectively removed as desired during the course of a synthesis.Examples of protecting groups can be found in Greene and Wuts, asmentioned above, and additionally, in Harrison et al., Compendium ofSynthetic Organic Methods, Vols. 1-8, 1971-1996, John Wiley & Sons, NY.Representative amino protecting groups include, but are not limited to,formyl, acetyl, trifluoroacetyl, benzyl, benzyloxycarbonyl (“CBZ”),tert-butoxycarbonyl (“Boc”), trimethylsilyl (“TMS”),2-trimethylsilyl-ethanesulfonyl (“TES”), trityl and substituted tritylgroups, allyloxycarbonyl, 9-fluorenylmethyloxycarbonyl (“FMOC”),nitro-veratryloxycarbonyl (“NVOC”) and the like. Representative hydroxylprotecting groups include, but are not limited to, those where thehydroxyl group is either acylated to form acetate and benzoate esters oralkylated to form benzyl and trityl ethers, as well as alkyl ethers,tetrahydropyranyl ethers, trialkylsilyl ethers (e.g., TMS or TIPPSgroups) and allyl ethers.

A specific embodiment of Scheme (I) utilizing 5-fluorouracil (Aldrich#32, 937-1) as a starting material is illustrated in Scheme (Ia), below:

In Scheme (Ia), ring A, (R²)_(p), (R³)_(q), W, Y, Z¹, Z² and Z³ are aspreviously defined for Scheme (I). Asymmetric2N,4N-disubstituted-5-fluoro-2,4-pyrimidinediamine A-11 can be obtainedby reacting 2,4-dichloro-5-fluoropyrimidine A-9 with one equivalent ofamine A-3 (to yield 2-chloro-N4-substituted-5-fluoro-4-pyrimidineamineA-10) followed by one or more equivalents of amine A-5.

In another exemplary embodiment, the 2,4-pyrimidinediamine compounds ofthe invention can be synthesized from substituted or unsubstitutedcytosines as illustrated in Schemes (IIa) and (IIb), below:

In Schemes (IIa) and (IIb), ring A, (R²)_(p), (R³)_(q), W, X, Y, Z¹, Z²and Z³ are as previously defined for Scheme (I) and PG represents aprotecting group. Referring to Scheme (IIa), the C4 exocyclic amine ofcytosine A-12 is first protected with a suitable protecting group PG toyield N4-protected cytosine A-13. For specific guidance regardingprotecting groups useful in this context, see Vorbrüggen andRuh-Pohlenz, 2001, Handbook of Nucleoside Synthesis, John Wiley & Sons,NY, pp. 1-631 (“Vorbrüggen”). Protected cytosine A-13 is halogenated atthe C2 position using a standard halogenation reagent under standardconditions to yield 2-chloro-4N-protected-4-pyrimidineamine A-14.Reaction with amine A-5 gives A-15, which on deprotection of the C4exocyclic amine, gives A-16. Reaction of A-16 with amine A-3 yields2,4-pyrimidinediamine derivative A-6.

Alternatively, referring to Scheme (IIb), cytosine A-12 can be reactedwith amine A-3 or protected amine A-19 to yield N4-substituted cytosineA-17 or A-20, respectively. These substituted cytosines may then behalogenated as previously described, deprotected (in the case ofN4-substituted cytosine A-20) and reacted with amine A-5 to yield a2,4-pyrimidinediamine A-6.

Commercially-available cytosines that can be used as starting materialsin Schemes (IIa) and (IIb) include, but are not limited to, cytosine(Aldrich #14, 201-8; CAS Registry 71-30-7); N⁴-acetylcytosine (Aldrich#37, 791-0; CAS Registry 14631-20-0); 5-fluorocytosine (Aldrich #27,159-4; CAS Registry 2022-85-7); and 5-(trifluoromethyl)-cytosine. Othersuitable cytosines useful as starting materials in Schemes (IIa) areavailable from General Intermediates of Canada, Inc., Edmonton, Calif.and/or Interchim, Cedex, France, or can be prepared using standardtechniques. Myriad textbook references teaching suitable syntheticmethods are provided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention can be synthesized from substituted orunsubstituted 2-amino-4-pyrimidinols as illustrated in Scheme (III),below:

In Scheme (III), ring A, (R²)_(p), (R³)_(q), W, X, Y, Z¹, Z² and Z³ areas previously defined for Scheme (I) and LG is a leaving group asdiscussed in more detail in connection with Scheme IV, infra. Referringto Scheme (III), 2-amino-4-pyrimidinol A-22 is reacted with arylatingagent A-23 to yield N2-substituted-4-pyrimidinol A-24, which is thenhalogenated as previously described to yieldN2-substituted-4-halo-2-pyrimidineamine A-25. Further reaction withamine A-3 affords a 2,4-pyrimidinediamine derivative A-6.

Suitable commercially-available 2-amino-4-pyrimidinols A-22 that can beused as starting materials in Scheme (III) are available from GeneralIntermediates of Canada, Inc., Edmonton, Calif. and/or Interchim, Cedex,France, or can be prepared using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

Alternatively, the 2,4-pyrimidinediamine compounds of the invention canbe prepared from substituted or unsubstituted 4-amino-2-pyrimidinols asillustrated in Scheme (IV), below:

In Scheme (IV), ring A, (R²)_(p), (R³)_(q), W, X, Y, Z¹, Z² and Z³ areas previously defined for Scheme (I). Referring to Scheme (IV), theC2-hydroxyl of 4-amino-2-pyrimidinol A-26 is more reactive towardsnucleophiles than the C4-amino such that reaction with amine A-5 yieldsN2-substituted-2,4-pyrimidinediamine A-27. Subsequent reaction withcompound A-28, which includes a suitable leaving group, or amine A-3yields a 2,4-pyrimidinediamine derivative A-6. Compound A-28 may includevirtually any leaving group that can be displaced by the C4-amino ofN2-substituted-2,4-pyrimidinediamine A-27. Suitable leaving groupsinclude, but are not limited to, halogens, methanesulfonyloxy (mesyloxy;“OMs”), trifluoromethanesulfonyloxy (“OTf”) and p-toluenesulfonyloxy(tosyloxy; “OTs”), benzene sulfonyloxy (“besylate”) and m-nitro benzenesulfonyloxy (“nosylate”). Other suitable leaving groups will be apparentto those of skill in the art.

Substituted 4-amino-2-pyrimidinol starting materials can be obtainedcommercially or synthesized using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra.

In still another exemplary embodiment, the 2,4-pyrimidinediaminecompounds of the invention can be prepared from2-chloro-4-aminopyrimidines or 2-amino-4-chloropyrimidines asillustrated in Scheme (V), below:

In Scheme (V), ring A, (R²)_(p), (R³)_(q), W, X, Y, Z¹, Z² and Z³ are asdefined for Scheme (I) and leaving group is as defined for Scheme (IV).Referring to Scheme (V), 2-amino-4-chloropyrimidine A-29 is reacted withamine A-3 to yield 4N-substituted-2,4-pyrimidinediamine A-30 which,following reaction with compound A-23 or amine A-5, yields aN2,N4-2,4-pyrimidinediamine derivative A-6. Alternatively,2-chloro-4-amino-pyrimidine A-31 can be reacted with compound A-28 togive compound A-32 which on reaction with amine A-5 yields A-6.

A variety of pyrimidines A-29 and A-31 suitable for use as startingmaterials in Scheme (V) are commercially available from GeneralIntermediates of Canada, Inc., Edmonton, Calif. and/or Interchim, Cedex,France, or can be prepared using standard techniques. Myriad textbookreferences teaching suitable synthetic methods are provided infra

Alternatively, 4-chloro-2-pyrimidineamines A-29 can be prepared asillustrated in Scheme (Va):

In Scheme (Va), X is as previously defined for Scheme I. In Scheme (Va),dialdehyde

A-33 is reacted with guanidine to yield 2-pyrimidineamine A-34. Reactionwith a peracid such as m-chloroperbenzoic acid, trifluoroperacetic acidor urea hydrogen peroxide complex yields N-oxide A-35, which is thenhalogenated to give 4-chloro-2-pyrimidineamine A-29. The corresponding4-halo-2-pyrimidineamines can be obtained by using suitable halogenationreagents.

In yet another exemplary embodiment, the 2,4-pyrimidinediamine compoundsof the invention can be prepared from substituted or unsubstituteduridines as illustrated in Scheme (VI), below:

In Scheme (VI), ring A, (R²)_(p), (R³)_(q), W, X, Y, Z¹, Z² and Z³ areas previously defined for Scheme (I) and PG represents a protectinggroup, as discussed in connection with Scheme (IIb). According to Scheme(VI), uridine A-36 has a C4 reactive center such that reaction withamine A-3 or protected amine A-19 yields N4-substituted cytidine A-37 orA-38, respectively. Acid-catalyzed deprotection of N4-substituted A-37or A-38 (when “PG” represents an acid-labile protecting group) yieldsN4-substituted cytosine A-39, which can be subsequently halogenated atthe C2-position and reacted with amine A-5 to yield a2,4-pyrimidinediamine derivative A-6.

Cytidines may also be used as starting materials in an analogous manner,as illustrated in Scheme (VII), below:

In Scheme (VII), ring A, (R²)_(p), (R³)_(q), W, X, Y, Z¹, Z² and Z³ areas previously defined in Scheme (I) and PG represents a protecting groupas discussed above. Referring to Scheme (VII), like uridine A-36,cytidine A-40 has a C4 reactive center such that reaction with amine A-3or protected amine A-19 yields N4-substituted cytidine A-37 or A-38,respectively. These cytidines A-37 and A-38 are then treated aspreviously described for Scheme (VI) to yield a 2,4-pyrimidinediaminederivative A-6.

Although Schemes (VI) and (VII) are exemplified with ribosylnucleosides,skilled artisans will appreciate that the corresponding 2′-deoxyribo and2′,3′-dideoxyribo nucleosides, as well as nucleosides including sugarsor sugar analogs other than ribose, would also work.

Numerous uridines and cytidines useful as starting materials in Schemes(VI) and (VII) are known in the art, and include, by way of example andnot limitation, 5-trifluoromethyl-2′-deoxycytidine (Chem. Sources #ABCRF07669; CAS Registry 66, 384-66-5); 5-bromouridine (Chem. Sources Int'l2000; CAS Registry 957-75-5); 5-iodo-2′-deoxyuridine (Aldrich #1-775-6;CAS Registry 54-42-2); 5-fluorouridine (Aldrich #32, 937-1; CAS Registry316-46-1); 5-iodouridine (Aldrich #85, 259-7; CAS Registry 1024-99-3);5-(trifluoromethyl)uridine (Chem. Sources Int'l 2000; CAS Registry70-00-8); 5-trifluoromethyl-2′-deoxyuridine (Chem. Sources Int'l 2000;CAS Registry 70-00-8). Additional uridines and cytidines that can beused as starting materials in Schemes (VI) and (VII) are available fromGeneral Intermediates of Canada, Inc., Edmonton, Calif. and/orInterchim, Cedex, France, or can be prepared using standard techniques.Myriad textbook references teaching suitable synthetic methods areprovided infra.

Although many of the synthetic schemes discussed above do not illustratethe use of protecting groups, skilled artisans will recognize that insome instances certain substituents, such as, for example, R² and/or R⁴,may include functional groups requiring protection. The exact identityof the protecting group used will depend upon, among other things, theidentity of the functional group being protected and the reactionconditions used in the particular synthetic scheme, and will be apparentto those of skill in the art. Guidance for selecting protecting groups,their attachment and removal suitable for a particular application canbe found, for example, in Greene & Wuts, supra.

Prodrugs as described herein can be prepared by routine modification ofthe above-described methods. Alternatively, such prodrugs can beprepared by reacting a suitably protected 2,4-pyrimidinediamine 6 with asuitable progroup. Conditions for carrying out such reactions and fordeprotecting the product to yield a prodrugs as described herein arewell-known.

Myriad references teaching methods useful for synthesizing pyrimidinesgenerally, as well as starting materials described in Schemes (I)-(VII),are known in the art. For specific guidance, the reader is referred toBrown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16 (Weissberger, A., Ed.), 1962, IntersciencePublishers, (A Division of John Wiley & Sons), New York (“Brown I”);Brown, D. J., “The Pyrimidines”, in The Chemistry of HeterocyclicCompounds, Volume 16, Supplement I (Weissberger, A. and Taylor, E. C.,Ed.), 1970, Wiley-Interscience, (A Division of John Wiley & Sons), NewYork (“Brown II”); Brown, D. J., “The Pyrimidines”, in The Chemistry ofHeterocyclic Compounds, Volume 16, Supplement II (Weissberger, A. andTaylor, E. C., Ed.), 1985, An Interscience Publication (John Wiley &Sons), New York (“Brown III”); Brown, D. J., “The Pyrimidines” in TheChemistry of Heterocyclic Compounds, Volume 52 (Weissberger, A. andTaylor, E. C., Ed.), 1994, John Wiley & Sons, Inc., New York, pp. 1-1509(“Brown IV”); Kenner, G. W. and Todd, A., in Heterocyclic Compounds,Volume 6, (Elderfield, R. C., Ed.), 1957, John Wiley, New York, Chapter7 (pyrimidines); Paquette, L. A., Principles of Modern HeterocyclicChemistry, 1968, W. A. Benjamin, Inc., New York, pp. 1-401 (uracilsynthesis pp. 313, 315; pyrimidinediamine synthesis pp. 313-316; aminopyrimidinediamine synthesis pp. 315); Joule, J. A., Mills, K. and Smith,G. F., Heterocyclic Chemistry, 3^(rd) Edition, 1995, Chapman and Hall,London, UK, pp. 1-516; Vorbrüggen, H. and Ruh-Pohlenz, C., Handbook ofNucleoside Synthesis, John Wiley & Sons, New York, 2001, pp. 1-631(protection of pyrimidines by acylation pp. 90-91; silylation ofpyrimidines pp. 91-93); Joule, J. A., Mills, K. and Smith, G. F.,Heterocyclic Chemistry, 4^(th) Edition, 2000, Blackwell Science, Ltd,Oxford, UK, pp. 1-589; and Comprehensive Organic Synthesis, Volumes 1-9(Trost, B. M. and Fleming, I., Ed.), 1991, Permagon Press, Oxford, UK.

Those of skill in the art will appreciate that the 2,4-pyrimidinediaminecompounds described herein may include functional groups that can bemasked with progroups to create prodrugs. Such prodrugs are usually, butneed not be, pharmacologically inactive until converted into theiractive drug form. Indeed, many of the 2,4-pyrimidinediamine compoundsdescribed in this invention include promoieties that are hydrolyzable orotherwise cleavable under conditions of use. For example, ester groupscommonly undergo acid-catalyzed hydrolysis to yield the parentcarboxylic acid when exposed to the acidic conditions of the stomach, orbase-catalyzed hydrolysis when exposed to the basic conditions of theintestine or blood. Thus, when administered to a subject orally,2,4-pyrimidinediamine compounds that include ester moieties can beconsidered prodrugs of their corresponding carboxylic acid, regardlessof whether the ester form is pharmacologically active.

The mechanism by which the progroup(s) metabolizes is not critical, andcan be caused by, for example, hydrolysis under the acidic conditions ofthe stomach, as described above, and/or by enzymes present in thedigestive tract and/or tissues or organs of the body. Indeed, theprogroup(s) can be selected to metabolize at a particular site withinthe body. For example, many esters are cleaved under the acidicconditions found in the stomach. Prodrugs designed to cleave chemicallyin the stomach to the active 2,4-pyrimidinediamine can employ progroupsincluding such esters. Alternatively, the progroups can be designed tometabolize in the presence of enzymes such as esterases, amidases,lipolases, phosphatases including ATPases and kinase etc. Progroupsincluding linkages capable of metabolizing in vivo are well-known, andinclude, by way of example and not limitation, ethers, thioethers,silylethers, silylthioethers, esters, thioesters, carbonates,thiocarbonates, carbamates, thiocarbamates, ureas, thioureas,carboxamides, etc. In some instances, a “precursor” group that isoxidized by oxidative enzymes such as, for example, cytochrome P450 ofthe liver, to a metabolizable group, can be selected.

In the prodrugs, any available functional moiety can be masked with aprogroup to yield a prodrug. Functional groups within the2,4-pyrimidinediamine compounds that can be masked with progroups forinclusion in a promoiety include, but are not limited to, amines(primary and secondary), hydroxyls, sulfanyls (thiols), carboxyls, etc.Myriad progroups suitable for masking such functional groups to yieldpromoieties that are cleavable under the desired conditions of use areknown in the art. All of these progroups, alone or in combinations, canbe included in the prodrugs.

In some embodiments of the 2,4-pyrimidinediamine compounds and methodsof using the compounds, the progroup(s) can be attached to any availableprimary or secondary amine, including, for example, the N2 nitrogen atomof the 2,4-pyrimidinediamine moiety, the N4 nitrogen atom of the2,4-pyrimidinediamine moiety, and/or a primary or secondary nitrogenatom included in a substituent on the 2,4-pyrimidinediamine compound.

In particular embodiments of the 2,4-pyrimidinediamine compounds andmethods of using the compounds, the prodrugs described herein are2,4-pyrimidinediamine compounds that are substituted at the N4 nitrogenof the 2,4-pyrimidinediamine moiety with a substituted or unsubstitutednitrogen-containing bicyclic ring that includes at least one progroup atone or more of: the nitrogen atom(s) of the bicyclic ring, the N2nitrogen of the 2,4-pyrimidinediamine moiety and/or the N4 nitrogen ofthe 2,4-pyrimidinediamine moiety.

As noted above, the identity of the progroup is not critical, providedthat it can be metabolized under the desired conditions of use, forexample under the acidic conditions found in the stomach and/or byenzymes found in vivo, to yield a the biologically active group, e.g.,the 2,4-substituted pyrimidinediamines as described herein. Thus,skilled artisans will appreciate that the progroup can comprisevirtually any known or later-discovered hydroxyl, amine or thiolprotecting group. Non-limiting examples of suitable protecting groupscan be found, for example, in Protective Groups in Organic Synthesis,Greene & Wuts, 2nd Ed., John Wiley & Sons, New York, 1991 (especiallypages 10-142 (alcohols, 277-308 (thiols) and 309-405 (amines) thedisclosure of which is incorporated herein by reference).

Additionally, the identity of the progroup(s) can also be selected so asto impart the prodrug with desirable characteristics. For example,lipophilic groups can be used to decrease water solubility andhydrophilic groups can be used to increase water solubility. In thisway, prodrugs specifically tailored for selected modes of administrationcan be obtained. The progroup can also be designed to impart the prodrugwith other properties, such as, for example, improved passive intestinalabsorption, improved transport-mediated intestinal absorption,protection against fast metabolism (slow-release prodrugs),tissue-selective delivery, passive enrichment in target tissues,targeting-specific transporters, etc. Groups capable of impartingprodrugs with these characteristics are well-known, and are described,for example, in Ettmayer et al., 2004, J. Med. Chem. 47(10):2393-2404,the disclosure of which is incorporated by reference. All of the variousgroups described in these references can be utilized in the prodrugsdescribed herein.

V. EXAMPLES

The invention is further understood by reference to the followingexamples, which are intended to be purely exemplary of the invention.The present invention is not limited in scope by the exemplifiedembodiments, which are intended as illustrations of single aspects ofthe invention only. Any methods that are functionally equivalent arewithin the scope of the invention. Various modifications of theinvention in addition to those described herein will become apparent tothose skilled in the art from the foregoing description. Suchmodifications fall within the scope of the appended claims.

In the examples below as well as throughout the application, thefollowing abbreviations have the following meanings. If not defined, theterms have their generally accepted meanings.

-   -   mL=milliliter    -   s=singlet    -   d=doublet    -   t=triplet    -   q=quartet    -   m=multiplet    -   dd=doublet of doublets    -   br=broad    -   nM=nanomolar    -   μg=microgram    -   ng=nanogram    -   MS=mass spectrum    -   LC=liquid chromatography    -   DMSO=dimethylsulfoxide    -   μL=microliter    -   mM=millimolar    -   rpm=revolutions per minute

Example 1

Synthesis ofN4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamineis provided for reference to one of ordinary skill in the art to morespecifically show how to make a 2,4-pyrimidinediamine

4-Nitrobenzylamine HCl (1.5 g), cyclopropanesulfonyl chloride (1 g) andtriethylamine (3 mL) were dissolved in dichloromethane (20 mL). Thereaction solution was stirred at rt overnight. The reaction mixture wasdiluted with 1N HCl aq. solution (50 mL) and water (100 mL). Thesolution was extracted with ethyl acetate (2×100 mL). The organicsolution was evaporated to giveN-cyclopropylsulfonyl-4-nitrobenzylamine. ¹H NMR (DMSO-d₆): δ 0.89 (d,7.8 Hz, 4H), 4.33 (d, J=6.6 Hz, 2H), 7.61 (d, J=8.7 Hz, 2H), 7.83 (t,J=6.6 Hz, 1H), 8.20 (d, 8.7 Hz, 2H).

N-Cyclopropylsulfonyl-4-nitrobenzylamine was dissolved in methanol (50mL) and to the solution was added 10% Pd—C. The reaction mixture wasplaced under hydrogen atmosphere (˜40 psi) and shaken for 1 h. Thecatalyst was filtered off over celite and washed with methanol (1 L) andwater (10 mL). The filtrate was evaporated to giveN-cyclopropylsulfonyl-4-aminobenzylamine. ¹H NMR (DMSO-d₆): δ 0.87 (m,4H), 2.37 (m, 1H), 3.96 (d, J=6.0 Hz, 2H), 4.99 (br, 2H), 6.49 (d, J=8.1Hz, 2H), 6.96 (d, J=8.4 Hz, 2H), 7.33 (t, J=6.0 Hz, 1H).

N-Cyclopropylsulfonyl-4-aminobenzylamine and2,6-dichloro-5-fluoropyrimidine (1.5 g) were dissolved in methanol (10mL) and water (2 mL). The reaction solution was stirred at rt overnight.The reaction solution was diluted with water (150 mL) and sonicated. Theprecipitate was filtered off, washed with water and dried to give2-chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-4-pyrimidineamine.¹H NMR (DMSO-d₆): δ 0.89 (m, 4H), 4.16 (d, J=6.3 Hz, 2H), 7.34 (d, J=8.4Hz, 2H), 7.60 (t, 1H), 7.61 (d, J=8.1 Hz, 2H), 8.29 (d, J=3.6 Hz, 1H),9.98 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ—192.77.

2-Chloro-N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-4-pyrimidineamine(80 mg) and 3,5-dimethylaniline (80 mg) were suspended in isopropanol (1mL) and TFA (5 drops). The solution was heated at 100° C. overnight. Thesolution was diluted with methanol (5 mL), sonicated and the precipitatewas filtered off to giveN4-(4-cyclopropylsulfonylaminomethyl)phenyl-N2-(3,5-dimethyl)phenyl-5-fluoro-2,4-pyrimidinediamine.¹H NMR (DMSO-d₆): δ 0.89 (m, 4H), 2.19 (s, 6H), 2.45 (m, 1H), 4.14 (d,J=6.3 Hz, 2H), 6.60 (s, 1H), 7.18 (s, 2H), 7.28 (d, J=8.4 Hz, 2H), 7.58(t, J=6.0 Hz, 1H), 7.71 (d, J=8.4 Hz, 2H), 8.11 (d, J=4.2 Hz, 1H), 9.28(br, 1H), 9.62 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ—163.21; LCMS:purity: 97.23%; MS (m/e): 442.78 (MH+).

The compounds listed below were made in a similar fashion to Example 1or by methods described herein or known to skilled artisans.

N4-(4-ethylsulfonylaminomethyl)phenyl-5-fluoro-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine(I-10) LCMS: purity: 98.40%; MS (m/e): 509.30 (MH+); ¹H NMR (DMSO-d₆): δ1.16 (t, J=7.2 Hz, 3H), 2.54 (d, J=4.2 Hz, 3H), 2.92 (q, J=7.2 Hz, 2H),4.11 (t, J=6.0 Hz, 2H), 4.22 (s, 2H), 6.84 (d, J=4.8 Hz, 1H), 7.21 (d,J=8.4 Hz, 2H), 7.30 (d, J=8.4 Hz, 2H), 7.56 (m, 1H), 7.60 (d, J=8.1 Hz,2H), 7.72 (d, J=8.4 Hz, 2H), 8.12 (d, J=3.9 Hz, 1H), 9.46 (br, 1H), 9.62(br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ—201.99.

N4-(3-ethylsulfonylaminomethyl)phenyl-5-fluoro-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine(I-12) LCMS: purity: 85.58%; MS (m/e): 509.40 (MH+); ¹H NMR (DMSO-d₆): δ1.16 (t, J=7.2 Hz, 3H), 2.53 (d, J=4.8 Hz, 3H), 2.94 (q, J=7.2 Hz, 2H),4.13 (t, 6.0 Hz, 2H), 4.20 (s, 2H), 6.82 (d, J=4.5 Hz, 1H), 7.06 (d,J=8.1 Hz, 1H), 7.18 (d, J=8.4 Hz, 2H), 7.30 (t, J=7.5 Hz, 1H), 7.59 (m,1H), 7.63 (d, J=8.4 Hz, 2H), 7.70 (m, 2H), 8.10 (d, J=3.6 Hz, 1H), 9.19(br, 1H), 9.42 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ—202.66.

N4-[4-(2-ethylsulfonylamino)ethyl]phenyl-5-fluoro-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine (I-15) LCMS: purity: 96.49%; MS(m/e): 523.43 (MH+); ¹H NMR (DMSO-d₆): δ 1.14 (t, J=7.5 Hz, 3H), 2.61(d, J=4.2 Hz, 3H), 2.74 (t, J=7.5 Hz, 2H), 2.94 (q, J=7.5 Hz, 2H), 3.13(t, J=6.0 Hz, 2H), 4.21 (s, 2H), 6.82 (d, J=6.0 Hz, 1H), 7.12 (d, J=4.2Hz, 1H), 7.18 (d, J=8.7 Hz, 2H), 7.19 (d, J=8.7 Hz, 2H), 7.64 (d, J=8.7Hz, 2H), 7.68 (d, J=8.7 Hz, 2H), 8.07 (d, J=3.3 Hz, 1H), 9.24 (br, 1H),9.30 (br, 1H); ¹⁹F NMR (282 MHz, DMSO-d₆): δ—202.99.

N4-[4-(N-ethylsulfonyl-N-propyl)aminomethyl]phenyl-5-fluoro-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine (I-9) LCMS: purity: 95.55%;MS (m/e): 551.45 (MH+); ¹H NMR (DMSO-d₆): δ 0.74 (t, J=7.2 Hz, 3H), 1.16(t, J=7.5 Hz, 3H), 1.41 (q, J=7.8 Hz, 2H), 2.53 (d, J=5.1 Hz, 3H), 3.11(m, 4H), 4.19 (s, 2H), 4.33 (s, 2H), 6.83 (d, J=4.8 Hz, 1H), 7.17 (d,J=8.7 Hz, 2H), 7.31 (d, J=8.4 Hz, 2H), 7.64 (d, J=8.1 Hz, 2H), 7.78 (d,J=8.1 Hz, 2H), 8.09 (d, J=3.0 Hz, 1H), 9.27 (br, 1H), 9.38 (br, 1H); ¹⁹FNMR (282 MHz, DMSO-d₆): δ—202.81.

N4-(4-cyclopropylsulfonylaminomethyl)phenyl-5-fluoro-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine (I-8) LCMS: purity: 91.34%;MS (m/e): 521.14 (MH+); ¹H NMR (DMSO-d₆): δ 0.90 (m, 4H), 2.54 (d, J=4.5Hz, 3H), 4.16 (d, J=6.6 Hz, 2H), 4.22 (s, 2H), 6.84 (d, J=4.8 Hz, 1H),7.20 (d, J=8.7 Hz, 2H), 7.30 (d, J=8.7 Hz, 2H), 7.60 (m, 1H), 7.62 (d,J=9.0 Hz, 2H), 7.73 (d, J=8.7 Hz, 2H), 8.11 (d, J=3.6 Hz, 1H), 9.38 (br,1H), 9.51 (br, 1H).

N4-(4-ethylsulfonylaminomethyl)phenyl-5-methyl-N2-(4-methylaminosulfonylmethyl)phenyl-2,4-pyrimidinediamine (I-2) LCMS: purity: 93.45%; MS(m/e): 505.48 (MH+); ¹H NMR (DMSO-d₆): δ 1.17 (t, J=7.2 Hz, 3H), 2.16(s, 3H), 2.55 (d, J=5.1 Hz, 3H), 2.95 (q, J=7.2 Hz, 2H), 4.16 (t, J=6.3Hz, 2H), 4.26 (s, 2H), 6.87 (d, J=4.8 Hz, 1H), 7.23 (d, J=8.7 Hz, 2H),7.35 (d, J=8.7 Hz, 2H), 7.42 (d, J=9.0 Hz, 2H), 7.53 (d, J=8.7 Hz, 2H),7.61 (t, J=5.7 Hz, 1H), 7.86 (s, 1H), 9.56 (br, 1H), 10.01 (br, 1H).

N2,N4-bis(4-cyclopropylsulfonylaminomethyl)phenyl-5-methyl-2,4-pyrimidinediamine(II-1) LCMS: purity: 98.81%; MS (m/e): 543.42 (MH+); ¹H NMR (DMSO-d₆): δ0.88 (m, 8H), 2.10 (s, 3H), 2.43 (m, 2H), 4.08 (d, J=6.3 Hz, 2H), 4.17(d, J=6.0 Hz, 2H), 7.14 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.7 Hz, 2H), 7.45(t, J=6.3 Hz, 1H), 7.58 (t, J=6.6 Hz, 1H), 7.62 (d, J=8.4 Hz, 2H), 7.68(d, J=8.4 Hz, 2H), 7.86 (s, 1H), 8.25 (br, 1H), 8.95 (br, 1H);

N2,N4-bis[4-(2-cyclopropylsulfonylamino)ethyl]phenyl-5-methyl-2,4-pyrimidinediamine (II-2) LCMS: purity: 97.61%; MS (m/e): 571.43 (MH+); ¹H NMR(DMSO-d₆): δ 0.89 (m, 8H), 2.15 (s, 3H), 2.75 (t, J=7.5 Hz, 2H), 2.81(t, J=7.8 Hz, 2H), 3.20 (m, 4H), 7.11 (m, 2H), 7.14 (d, J=8.4 Hz, 2H),7.26 (d, J=8.7 Hz, 2H), 7.32 (d, J=8.1 Hz, 2H), 7.48 (d, J=8.4 Hz, 2H),7.81 (s, 1H), 9.61 (br, 1H), 10.06 (br, 1H).

N2,N4-bis[4-(pyrid-3-yl)sulfonylaminomethyl]phenyl-5-methyl-2,4-pyrimidinediamine(II-3) LCMS: purity: 94.00%; MS (m/e): 617.15 (MH+); ¹H NMR (DMSO-d₆): δ2.15 (s, 3H), 4.02 (d, J=5.4 Hz, 2H), 4.09 (d, J=5.7 Hz, 2H), 7.11 (d,J=7.5 Hz, 2H), 7.23 (d, J=9.0 Hz, 2H), 7.29 (d, J=9.3 Hz, 2H), 7.45 (d,J=8.7 Hz, 2H), 7.54 (m, 2H), 7.82 (s, 1H), 8.09 (t, 2H), 8.36 (t, 1H),8.44 (t, 1H), 8.74 (t, 2H), 8.88 (d, 1H), 8.92 (d, 1H), 9.51 (br, 1H),9.97 (br, 1H).

N2,N4-bis(4-cyclopropylsulfonylaminomethyl)phenyl-5-trifluoromethyl-2,4-pyrimidinediamine(II-4) LCMS: purity: 100%; MS (m/e): 597.29 (MH+); ¹H NMR (DMSO-d₆): δ0.88 (m, 8H), 2.41 (m, 2H), 4.08 (d, J=5.1 Hz, 2H), 4.23 (d, J=6.0 Hz,2H), 7.10 (d, J=8.4 Hz, 2H), 7.35 (d, J=8.4 Hz, 2H), 7.43 (m, 5H), 7.66(t, J=6.0 Hz, 1H), 8.35 (s, 1H), 8.87 (br, 1H), 9.78 (br, 1H); ¹⁹F NMR(282 MHz, DMSO-d₆): δ—60.39.

I-3N2-(3-Aminosulfonylmethylphenyl)-5-fluoro-N4-[4-(prop-2-ynyloxy)phenyl]-2,4-pyrimidinediamineLCMS: purity: 96%; MS (m/e): 428 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.94 (s,1H), 9.83 (s, 1H), 8.17 (d, J=4.5 Hz, 1H), 7.66-7.56 (m, 3H), 7.45 (s,1H), 7.26 (t, J=7.8 Hz, 1H), 7.03-6.95 (m, 3H), 6.84 (s, 2H), 4.80 (d,J=2.4 Hz, 2H), 4.18 (s, 2H), 3.60-3.58 (m, 1H).

I-14 N2-(3-Aminosulfonylmethylphenyl)-5-fluoro-N4-{4-[(prop-2-ynyloxy)carbonylaminomethyl]phenyl}-2,4-pyrimidinediamine: LCMS: purity: 97%; MS(m/e): 486 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.74 (s, 1H), 9.58 (s, 1H), 8.13(d, J=4.2 Hz, 1H), 7.92-7.86 (m, 1H), 7.70-7.60 (m, 3H), 7.49 (s, 1H),7.25-7.18 (m, 3H), 6.96 (d, J=7.8 Hz, 1H), 6.82 (s, 2H), 4.63 (d, J=2.1Hz, 2H), 4.19-4.15 (m, 4H), 3.48 (t, J=2.1 Hz, 1H).

IV-3N2-(3-Aminosulfonylmethylphenyl)-5-fluoro-N4-[1-(propyn-3-yl)indol-5-yl]-2,4-pyrimidinediamine:LCMS: purity: 98%; MS (m/e): 452 (MH⁺); ¹H NMR (DMSO-d₆): δ 10.27 (s,1H), 10.00 (s, 1H), 8.19 (d, J=5.1 Hz, 1H), 7.83 (d, J=1.2 Hz, 1H), 7.58(d, J=9.0 Hz, 1H), 7.52 (d, J=9.0 Hz, 1H), 7.42 (d, J=3.3 Hz, 1H), 7.38(dd, J=1.8 and 8.1 Hz, 1H), 7.34 (s, 1H), 7.17 (t, J=7.8 Hz, 1H), 7.00(d, J=7.2 Hz, 1H), 6.80 (s, 2H), 6.43 (d, J=2.7 Hz, 1H), 5.10 (d, J=2.1Hz, 2H), 4.09 (s, 2H), 3.42 (t, J=2.1 Hz, 1H).

III-1N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamineLCMS: purity: 95%; MS (m/e): 480 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.40 (s,1H), 9.14 (s, 1H), 8.11 (d, J=3.6 Hz, 1H), 7.54 (dd, J=2.4 and 8.4 Hz,1H), 7.50 (d, J=2.1 Hz, 1H), 7.46-7.40 (m, 2H), 7.30 (d, J=8.7 Hz, 1H),6.99 (d, J=8.1 Hz, 1H), 6.85 (s, 2H), 4.10 (s, 2H), 3.76 (s, 3H), 3.24(t, J=6.0 Hz, 2H), 2.82 (t, J=5.4 Hz, 2H).

III-2N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-[4-(cyclopropylsulfonylaminomethyl)phenyl]-5-fluoro-2,4-pyrimidinediamine:LCMS: purity: 97%; MS (m/e): 549 (MH+); ¹H NMR (DMSO-d6): δ 9.31 (s,1H), 9.13 (s, 1H), 8.07 (d, J=3.9 Hz, 1H), 7.73 (d, J=8.7 Hz, 2H),7.53-7.50 (m, 2H), 7.42-7.37 (m, 1H), 7.30 (d, J=8.7 Hz, 2H), 7.00 (d,J=8.7 Hz, 1H), 6.86 (s, 2H), 4.17 (d, J=4.5 Hz, 2H), 4.09 (s, 2H),3.26-3.21 (m, 2H), 2.81 (t, J=5.7 Hz, 2H), 2.45-2.42 (m, 1H), 0.92-0.86(m, 4H);

III-3N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine:LCMS: purity: 99%; MS (m/e): 515 (MH+); ¹H NMR (DMSO-d6): δ 11.05 (s,1H), 9.17 (s, 1H), 9.15 (s, 1H), 8.11 (d, J=4.2 Hz, 1H), 7.63-7.58 (m,1H), 7.47-7.43 (m, 1H), 7.41 (s, 1H), 7.36 (d, J=8.4 Hz, 1H), 6.97 (d,8.4 Hz, 1H), 6.84 (s, 2H), 4.10 (s, 2H), 3.23 (t, J=5.1 Hz, 2H),2.84-2.77 (m, 2H), 1.42 (s, 6H).

I-3:N2-[3-(Aminosulfonylmethylene)phenyl]-N4-(3-chloro-4-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 98%; MS (m/e): 438 (MH⁺); ¹H NMR (DMSO-d6): δ 9.30 (d, 1H,J=8.4 Hz), 8.08 (d, 1H, J=3.9 Hz), 7.82 (d, 1H, J=2.7 Hz), 7.70 (m, 2H),7.53 (s, 1H), 7.20 (t, 1H, J=7.8 Hz), 7.12 (d, 1H, J=9.0 Hz), 6.90 (d,1H, J=7.5 Hz), 6.81 (s, 2H), 4.13 (s, 2H), 3.84 (s, 3H).

I-5:N2-[3-(Aminosulfonylmethylene)phenyl]-N4-(4-chloro-3-methoxyphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 97%; MS (m/e): 438 (MH⁺); ¹H NMR (DMSO-d6): δ 9.44 (s,1H), 9.29 (s, 1H), 8.12 (m, 1H), 7.18 (d, 1H, J=8.1 Hz), 7.54 (s, 2H),7.50 (s, 1H), 7.31 (m, 1H), 7.19 (t, 1H, J=7.8 Hz), 6.91 (d, 1H, J=7.5Hz), 6.81 (s, 2H), 4.14 (s, 2H), 3.75 (s, 3H).

I-13:N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-(4-tertiarybutylphenyl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 99%; MS (m/e): 430 (MH⁺); ¹H NMR (DMSO-d6): δ 9.28 (s,1H), 9.23 (s, 1H), 8.07 (d, 1H, J=3.9 Hz), 7.68 (d, 2H, J=8.7 Hz), 7.62(s, 2H), 7.34 (d, 2H, J=8.4 Hz), 7.17 (t, 1H, J=7.5 Hz), 6.90 (d, 1H,J=7.5 Hz), 6.81 (s, 2H), 4.13 (s, 2H), 1.29 (s, 9H).

I-1:N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-(4-cyanomethyleneoxyphenyl)-2,4-pyrimidinediamine. LCMS: purity: 98%; MS (m/e): 429 (MH⁺);¹H NMR (DMSO-d6): δ 9.30 (s, 1H), 9.24 (s, 1H), 8.07 (d, 1H, J=3.6 Hz),7.73 (m, 3H), 7.56 (s, 1H), 7.20 (t, 1H, J=8.1 Hz), 7.05 (d, 2H, J=9.0Hz), 6.89 (d, 1H, J=7.5 Hz), 6.81 (s, 2H), 5.15 (s, 2H), 4.14 (s, 2H).

IV-4:N2-[3-(Aminosulfonylmethylene)phenyl]-N4-(3-cyanomethylene-1H-indol-5-yl)-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 95%; MS (m/e): 452 (MH⁺); ¹H NMR (DMSO-d6): δ 11.07 (s,1H), 9.30 (s, 1H), 9.06 (s, 1H), 8.03 (d, 1H, J=3.9 Hz), 7.86 (s, 1H),7.70 (d, 1H, 8.1 Hz), 7.51 (s, 1H), 7.38 (m, 3H), 7.06 (t, 1H, J=7.8Hz), 6.85 (d, 1H, J=7.8 Hz), 6.74 (s, 2H), 4.06 (s, 2H), 3.98 (s, 2H).

I-20:N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[(1-methylpyrazolyl-5-aminocarbonylmethylene)phenyl]-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 97%; MS (m/e): 511 (MH⁺); ¹H NMR (DMSO-d6): δ 10.54 (s,1H), 9.30 (s, 1H), 9.21 (s, 1H), 8.05 (d, 1H, J=3.3 Hz), 7.71 (s, 1H),7.69 (d, 1H, J=8.1 Hz), 7.56 (s, 1H), 7.50 (d, 1H, J=1.5 Hz), 7.24 (d,2H, J=8.4 Hz), 7.16 (t, 1H, J=8.1 Hz), 6.88 (d, 1H, J=8.1 Hz), 6.85 (s,2H), 6.38 (d, 2H, J=1.15 Hz), 4.14 (s, 2H), 3.71 (s, 3H), 3.56 (s, 2H).

I-11:N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(N-methylaminosulfonylmethylene)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 98%; MS (m/e): 481 (MH⁺); ¹HNMR (DMSO-d6): δ 8.11 (d, 2H,J=3.6 Hz), 7.88 (d, 1H, J=7.2 Hz), 7.72 (s, 2H), 7.54 (s, 1H), 7.33 (t,1H, J=8.4 Hz), 7.23 (t, 1H, J=7.8 Hz), 7.08 (d, 1H, J=7.2 Hz), 6.91 (d,2H, 6.9 Hz), 6.82 (s, 2H), 4.29 (s, 2H), 4.15 (s, 2H), 2.55 (s, 3H).

I-7:N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(N,N-dimethylaminosulfonylmethylene)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 99%; MS (m/e): 495 (MH⁺); ¹HNMR (DMSO-d6): δ 8.11 (d, 1H,J=2.4 Hz), 7.92 (d, 1H, J=6.6 Hz), 7.75 (s, 1H), 7.72 (d, 1H, J=8.1 Hz),7.54 (s, 1H), 7.34 (t, 1H, J=8.1 Hz), 7.23 (t, 1H, J=8.7 Hz), 7.12 (d,1H, J=7.2 Hz), 6.91 (d, 1H, J=6.6 Hz), 6.89 (s, 2H), 4.37 (s, 2H), 4.10(s, 3H), 2.70 (s, 3H).

I-21:N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(1-methylpiperidin-4-ylaminosulfonylmethylene)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 93%; MS (m/e): 550 (MH⁺); ¹HNMR (DMSO-d6): δ 9.54 (d, 1H,J=7.5 Hz), 9.32 (s, 1H), 8.39 (s, 1H), 8.17 (t, 1H), 7.88 (m, 3H), 7.61(s, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.16 (m, 1H), 6.92 (d, 2H, J=7.8Hz), 4.44 (s, 2H), 4.35 (s, 2H), 2.6 (m, 1H), 2.11 (s, 3H), 2.03 (bm,4H), 1.85 (m, 5H).

I-16:N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[4-(N-methylaminosulfonylmethylene)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 88%; MS (m/e): 481 (MH⁺); ¹HNMR (DMSO-d6): δ 9.30 (s, 1H),8.11 (d, 1H, J=3.6 Hz), 7.83 (d, 2H, J=8.1 Hz), 7.58 (s, 1H), 7.32 (d,2H, J=8.4 Hz), 7.21 (t, 1H, J=7.8 Hz), 6.91 (d, 2H, J=6.9 Hz), 4.29 (s,2H), 4.16 (s, 2H), 2.56 (s, 3H).

I-18:N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(N-methylaminosulfonyl)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 99%; MS (m/e): 467 (MH⁺); ¹HNMR (DMSO-d6): δ 8.38 (d, 1H,J=7.5 Hz), 8.15 (d, 1H, J=3.3 Hz), 7.96 (s, 1H), 7.72 (d, 1H, J=8.1 Hz),7.55 (t, 2H, J=7.8 Hz), 7.45 (d, 2H, J=8.4 Hz), 7.22 (d, 1H, J=7.5 Hz),6.92 (d, 1H, J=7.2 Hz), 6.81 (s, 2H), 4.15 (s, 2H), 2.45 (s, 3H).

I-17:N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(N,N-dimethylaminosulfonyl)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 98%; MS (m/e): 481 (MH⁺); ¹HNMR (DMSO-d6): δ 9.70 (s, 1H),9.32 (s, 1H), 8.56 (d, 1H, J=6.0 Hz), 8.17 (d, 1H, J=3.6 Hz), 7.84 (s,1H), 7.70 (d, 1H, J=7.5 Hz), 7.61 (s, 1H), 7.58 (d, 2H, J=7.5 Hz), 7.40(d, 1H, J=8.4 Hz), 7.22 (t, 1H, J=7.5 Hz), 6.92 (d, 1H, J=7.8 Hz), 6.81(s, 2H), 4.15 (s, 2H), 2.62 (s, 6H).

I-6:N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(N-cyclopropylamino-sulfonylmethylene)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 97%; MS (m/e): 507 (MH⁺); ¹HNMR (DMSO-d6): δ 9.45 (s, 1H),9.21 (s, 1H), 8.11 (d, 1H, J=3.9 Hz), 7.88 (d, 1H, J=8.1 Hz), 7.74 (d,2H, J=8.1 Hz), 7.54 (s, 1H), 7.47 (d, 1H, J=2.1 Hz), 7.33 (t, 1H, J=8.1Hz), 7.23 (t, 1H, J=7.8 Hz), 7.09 (d, 1H, J=7.8 Hz), 6.91 (d, 1H, J=7.5Hz), 6.82 (s, 2H), 4.33 (s, 2H), 4.14 (s, 2H), 2.49 (s, 1H), 0.53 (m,4H).

IV-1:N2-[3-(Aminosulfonylmethylene)phenyl]-N4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 96%; MS (m/e): 475 (MH⁺); ¹H NMR (DMSO-d6): δ 11.07 (s,1H), 9.32 (s, 1H), 9.21 (d, 1H), 8.12 (d, 1H, J=3.6 Hz), 7.73 (d, 1H,J=8.1 Hz), 7.63 (d, 1H, J=8.4 Hz), 7.53 (s, 1H), 7.38 (d, 1H, J=8.1 Hz),7.18 (t, 1H, J=7.8 Hz), 6.90 (d, 1H, J=7.2 Hz), 6.81 (s, 2H), 4.15 (s,2H), 1.43 (s, 6H).

I-19:N2-[3-(Aminosulfonylmethylene)phenyl]-5-fluoro-N4-[3-(aminosulfonyl-methylene)phenyl]-2,4-pyrimidinediamine.LCMS: purity: 95%; MS (m/e): 468 (MH⁺); ¹HNMR (DMSO-d6): δ 9.43 (s, 1H),9.21 (s, 1H), 8.10 (d, 1H, J=3.9 Hz), 7.87 (d, 1H, 8.4 Hz), 7.75 (d, 1H,J=8.1 Hz), 7.68 (s, 1H), 7.54 (s, 1H), 7.32 (t, 1H, J=8.1 Hz), 7.20 (t,1H, J=8.1 Hz), 7.08 (d, 1H, J=7.5 Hz), 6.91 (d, 1H, J=7.5 Hz), 6.85 (s,2H), 6.81 (s, 2H), 4.24 (s, 2H), 4.15 (s, 2H).

V-4:N4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-N2-[3,3-dioxo-1H-benzo[e][1,3,4]oxathiazin-7-yl]-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 99%; MS (m/e): 488 (MH⁺); ¹HNMR (DMSO-d6): δ 11.07 (s,1H), 9.18 (d, 2H, J=6.6 Hz), 8.09 (d, 1H, J=3.0 Hz), 7.57 (d, 1H, J=8.1Hz), 7.36 (s, 1H), 7.33 (s, 1H), 7.18 (d, 1H, J=8.7 Hz), 6.60 (d, 1H,J=8.1 Hz), 4.95 (s, 2H).

V-1N2-(4-aminosulfonyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine:LCMS: purity: 90%; MS (m/e): 469 (MH⁺); ¹H NMR (DMSO-d6): δ 10.63 (s,1H), 9.68 (s, 1H), 9.44 (s, 1H), 8.18 (d, 1H, J=3.0 Hz), 7.63 (d, 2H,J=8.1 Hz), 7.61 (d, 2H, J=9.0 Hz), 7.30 (t, 1H, J=12 Hz), 7.09 (s, 2H),6.83 (m, 1H), 4.52 (s, 2H).

V-2N2-(3-aminosulfonyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine:LCMS: purity: 98%; MS (m/e): 469 (MH⁺); ¹H NMR (DMSO-d6): δ 9.46 (s,1H), 8.11 (d, 1H, J=3.3 Hz), 7.99 (s, 1H), 7.83 (d, 1H, J=7.2 Hz), 7.22(m, 4H), 6.48 (m, 1H), 6.83 (m, 1H), 4.31 (s, 2H).

V-3N2-(3-aminosulfonyl-4-methyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine:LCMS: purity: 97%; MS (m/e): 483 (MH⁺); ¹H NMR (DMSO-d6): δ 9.35 (s,1H), 8.08 (d, 1H, J=3.3 Hz), 8.02 (s, 2H), 7.77 (d, 2H, J=9.9 Hz), 7.19(s, 2H), 7.05 (d, 1H, J=9.3 Hz), 7.04 (d, 1H, J=8.4 Hz), 6.67 (m, 1H),4.33 (s, 2H).

IV-5:N2-(3-Aminosulfonylmethylenephenyl)-5-fluoro-N4-[2-(2-N-morpholinoethylaminoacrbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine:MS: purity: 93 MS (m/e): 571 MH⁺); ¹H NMR (DMSO-d6): δ 9.44 (s, 1H),9.26 (s, 1H), 8.65 (s, 1H), 8.23 (s, 1H), 8.08 (d, 1H, J=3.3 Hz), 7.59(s, 1H), 7.73 (s, 1H), 7.60 (d, 1H, J=9.3 Hz), 7.51 (s, 1H), 7.45 (s,1H), 7.15 (t, 1H, J=8.1 Hz), 6.89 (d, 1H, J=7.8 Hz), 6.80 (s, 2H), 4.11(s, 2H), 3.60 (bs, 4H), 3.43 (bs, 4H), 2.49 (m, 4H).

IV-2:N2-[3-(Aminosulfonylmethylene)phenyl]-N4-[2,2-dimethyl-3-oxo-4-methyl-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine.LCMS: purity: 94%; MS (m/e): 489 (MH⁻); ¹HNMR (DMSO-d6): δ 9.46 (s, 1H),9.37 (s, 1H), 8.15 (d, 1H, J=3.6 Hz), 8.81 (d, 1H, J=8.4 Hz), 7.73 (d,1H, J=8.4 Hz), 7.57 (s, 1H), 7.40 (d, 1H, J=8.7 Hz), 7.19 (t, 2H, J=7.8Hz), 6.91 (d, 1H, J=7.5 Hz), 6.18 (s, 2H), 4.16 (s, 2H), 1.43 (s, 6H).

5-Nitroisoindoline ¹H NMR (DMSO-d₆): δ 9.478 (bs, 1H), 8.289 (s, 1H),8.235-8.207 (d, J=8.4 Hz, 1H), 7.673-7.645 (d, J=8.4 Hz, 1H),4.622-4.604 (d, J=5.4 Hz, 4H).

2-(Cyclopropylsulfonyl)-5-nitroisoindoline LCMS: 269.01 (MH+); ¹H NMR(DMSO-d₆): δ 8.228 (s, 1H), 8.195-8.166 (d, J=8.7 Hz, 1H), 7.609-7.580(d, J=8.7 Hz, 1H), 4.768 (s, 4H), 2.777 (m, 1H), 0.998-0.943 (m, 4H).

2-(Cyclopropylsulfonyl)-isoindolin-5-amine LCMS: 239.21 (MH+); ¹H NMR(DMSO-d₆): δ 6.937-6.910 (d, J=8.1 Hz, 1H), 6.487 (bs, 1H), 6.452 (bs,1H), 5.090 (s, 2H), 4.494-4.461 (d, J=9.9 Hz, 4H), 2.777 (m, 1H),0.976-0.930 (m, 4H).

2-Chloro-N4-[(2-cycloproylsulfonyl)-isoindolin-5-yl]-5-fluoro-4-pyrimidineamineLCMS: 369.31 (MH+); ¹H NMR (DMSO-d₆): δ 10.050 (s, 1H), 8.291-8.261 (d,J=9 Hz, 1H), 7.603 (s, 1H), 7.581-7.552 (d, J=8.7 Hz, 1H), 7.330-7.303(d, J=8.1 Hz, 1H), 4.673-4.640 (d, J=9.9 Hz, 4H), 2.790 (m, 1H),1.001-0.951 (m, 4H).

2-Chloro-N4-[(2-cycloproylsulfonyl)-isoindolin-5-yl]-5-methyl-4-pyrimidineamine¹H NMR (DMSO-d₆): δ 8.893 (s, 1H), 8.020 (s, 1H), 7.537 (s, 1H),7.526-7.499 (d, J=8.1 Hz, 1H), 7.318-7.292 (d, J=7.8 Hz, 1H),4.670-4.646 (d, J=7.2, 4H), 2.808 (m, 1H), 2.155 (s, 3H), 1.014-0.959(m, 4H).

V-5:N2-(3-Benzyl-cyclopropanesulfonamide)-N4-(3,4-dihydroquinolin-1H-6-yl)-5-methyl-2,4-pyrimidinediamineMS (m/e): 479.01 (MH⁺); ¹H NMR (DMSO-d₆): δ□ 9.99 (s, 1H), 8.95 (s, 1H),8.15 (s, 1H), 7.82 (s, 1H), 7.65-7.64 (d, J=3.0 Hz, 1H), 7.51-7.45 (m,4H), 7.10 (m, 1H), 6.85-6.78 (m, 3H), 4.03 (s, 2H), 2.86-2.82 (t, 2H),2.07 (s, 3H), 0.88 (m, 4H).

VI-1:(+/−)-N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine¹H NMR (DMSO-d6): δ 9.20 (s, 1H), 8.40 (s, 1H), 8.06 (s, 1H), 7.99 (d,1H, J=7.2 Hz), 7.88 (s, 1H), 7.77 (d, 1H, J=7.6 Hz), 7.52-7.50 (m, 2H),7.33-7.17 (m, 5H), 4.79 (app qt, 1H, J=7.2 and 8.8 Hz), 2.99 (s, 3H),2.93-2.85 (m, 1H), 2.79-2.68 (m, 1H), 2.55-2.48 (m, 1H), 2.11 (s, 3H),1.94-1.85 (m, 1H).

VI-2:(+/−)-N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine¹H NMR (DMSO-d6): δ 9.33 (s, 1H), 8.48 (s, 1H), 7.91 (s, 1H), 7.79 (d,2H, J=8.5 Hz), 7.71 (d, 1H, J=8.3 Hz), 7.57-7.46 (m, 4H), 7.21 (d, 1H,J=8.2 Hz), 7.09 (s, 2H), 4.81 (app qt, 1H, J=7.6 and 8.5 Hz), 2.99 (s,3H), 2.96-2.88 (m, 1H), 2.81-2.71 (m, 1H), 2.55-2.48 (m, 1H), 2.11 (s,3H), 1.93-1.86 (m, 1H).

VI-3:(+/−)-N2-(3-Aminosulfonylphenyl)-5-methyl-N4-[1-(cyclopropylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine¹H NMR (DMSO-d6): δ 9.17 (s, 1H), 8.39 (s, 1H), 7.91 (s, 1H), 8.08 (s,1H), 7.98 (d, 1H, J=7.6 Hz), 7.89 (s, 1H), 7.74 (d, 1H, J=8.2 Hz), 7.55(s, 1H), 7.52 (d, 1H, J=8.2 Hz), 7.32-7.26 (m, 3H), 7.22 (s, 2H), 7.18(d, 1H, J=8.2 Hz), 4.81 (app qt, 1H, J=7.6 Hz), 2.93-2.55 (m, 3H), 2.10(s, 3H), 1.90-1.86 (m, 1H), 0.99-0.92 (m, 4H).

VI-5:(1R)-N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine¹H NMR (DMSO-d6): δ 9.17 (s, 1H), 8.38 (s, 1H), 8.06 (app m, 1H),8.01-7.96 (m, 1H), 7.88 (d, 1H, J=0.9 Hz), 7.77 (dd, 1H, J=1.8 and 7.9Hz), 7.52-7.49 (m, 2H), 7.34-7.30 (m, 2H), 7.23 (s, 2H), 7.17 (d, 1H,J=8.2 Hz), 4.82-4.75 (app qt, 1H, J=7.6 Hz), 2.99 (s, 3H), 2.89-2.84 (m,1H), 2.78-2.68 (m, 1H), 2.54-2.49 (m, 1H), 2.10 (s, 3H), 1.91-1.84 (m,1H).

VI-6:(1S)-N2-(4-Aminosulfonylphenyl)-5-methyl-N4-[1-(methylsulfonyl)aminoindan-6-yl]-2,4-pyrimidinediamine¹H NMR (DMSO-d6): δ 9.32 (s, 1H), 8.46 (s, 1H), 7.90 (s, 1H), 7.82 (d,2H, J=9.1 Hz), 7.72 (dd, 1H, J=1.8 and 8.5 Hz), 7.55 (d, 2H, J=9.1 Hz),7.46 (s, 2H), 7.20 (d, 1H, J=8.2 Hz), 7.08 (s, 2H), 4.86 (app qt, 1H,J=7.6 Hz), 2.99 (s, 3H), 2.98-2.87 (m, 1H), 2.81-2.70 (m, 1H), 2.58-2.55(m, 1H), 2.10 (s, 3H), 1.96-1.83 (m, 1H).

III-4:N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(4-(prop-2-ynyloxy)phenyl)-5-fluoro-2,4-pyrimidinediamineMS (m/e): 469 (MH⁺); ¹H NMR (DMSO-d₆): δ 9.09 (s, 1H), 9.07 (s, 1H),8.03 (d, 1H, J=3.9 Hz), 7.66 (d, 2H, J=8.7 Hz), 7.46-7.40 (m, 2H),7.00-6.91 (m, 3H), 6.86 (s, 2H), 4.77 (d, 2H, J=2.4 Hz), 4.10 (s, 2H),3.55 (t, 1H, J=2.4 Hz), 3.23 (t, 2H, J=4.2 Hz), 2.81 (t, 2H, J=5.7 Hz);LCMS: purity: 97%.

Example 2 Assay for Ramos B-Cell Line Stimulated with IL-4

B-cells stimulated with cytokine Interleukin-4 (IL-4) activate theJAK/Stat pathway through phosphorylation of the JAK family kinases,JAK-1 and JAK-3, which in turn phosphorylate and activate thetranscription factor Stat-6. One of the genes upregulated by activatedStat-6 is the low affinity IgE receptor, CD23. To study the effect ofinhibitors on the JAK family kinases, human Ramos B cells are stimulatedwith human IL-4.

The Ramos B-cell line was acquired from ATCC (ATCC Catalog No.CRL-1596). The cells were cultured in RPMI 1640 (Cellgro, MediaTech,Inc., Herndon, Va., Cat No. 10-040-CM) with 10% fetal bovine serum(FBS), heat inactivated (JRH Biosciences, Inc, Lenexa, Kans., Cat No.12106-500M) according to ATCC propagation protocol. Cells weremaintained at a density of 3.5×10⁵. The day before the experiment, RamosB-cells were diluted to 3.5×10⁵ cells/mL to ensure that they were in alogarithmic growth phase.

Cells were spun down and suspended in RPMI with 5% serum. 5×10⁴ cellswere used per point in a 96-well tissue culture plate. Cells werepre-incubated with compound or DMSO (Sigma-Aldrich, St. Louis, Mo., CatNo. D2650) vehicle control for 1 hour in a 37° C. incubator.

Cells were then stimulated with IL-4 (Peprotech Inc., Rocky Hill, N.J.,Cat No. 200-04) for a final concentration of 50 units/mL for 20-24hours. Cells were then spun down and stained with anti-CD23-PE (BDPharmingen, San Diego, Calif., Cat No. 555711) and analyzed by FACS.Detection was performed using a BD LSR I System Flow Cytometer,purchased from Becton Dickinson Biosciences of San Jose, Calif. The IC₅₀calculated based on the results of this assay are provided in Table VII.

Example 3 Primary Human T-Cell Proliferation Assay Stimulated with IL-2

Primary human T-cells derived from peripheral blood and pre-activatedthrough stimulation of the T-cell receptor and CD28, proliferate invitro in response to the cytokine Interleukin-2 (IL-2). Thisproliferative response is dependent on the activation of JAK-1 and JAK-3tyrosine kinases, which phosphorylate and activate the transcriptionfactor Stat-5.

Human primary T cells were prepared as follows. Whole blood was obtainedfrom a healthy volunteer, mixed 1:1 with PBS, layered on to FicollHypaque (Amersham Pharmacia Biotech, Piscataway, N.J., Catalog#17-1440-03) in 2:1 blood/PBS:ficoll ratio and centrifuged for 30 min at4° C. at 1750 rpm. The lymphocytes at the serum: ficoll interface wererecovered and washed twice with 5 volumes of PBS. The cells wereresuspended in Yssel's medium (Gemini Bio-products, Woodland, Calif.,Catalog #400-103) containing 40 U/mL recombinant IL2 (R and D Systems,Minneapolis, Minn., Catalog #202-IL (20 μg)) and seeded into a flaskpre-coated with 1 μg/mL anti-CD3 (BD Pharmingen, San Diego, Calif.,Catalog #555336) and 5 anti-CD28 (Immunotech, Beckman Coulter of BreaCalif., Catalog #IM1376). The primary T-cells were stimulated for 3-4days, then transferred to a fresh flask and maintained in RPMI with 10%FBS and 40 U/mL IL-2.

Primary T-cells were washed twice with PBS to remove the IL-2 andresuspended in Yssel's medium at 2×10⁶ cells/mL. 50 μL of cellsuspension containing 80 U/mL IL-2 was added to each well of a flatbottom 96 well black plate. For the unstimulated control, IL-2 wasomitted from the last column on the plate. Compounds were seriallydiluted in dimethyl sulfoxide (DMSO, 99.7% pure, cell culture tested,Sigma-Aldrich, St. Louis, Mo., Catalog No. D2650) from 5 mM in 3-folddilutions, and then diluted 1:250 in Yssel's medium. 50 μL of 2×compound was added per well in duplicate and the cells were allowed toproliferate for 72 hours at 37° C.

Proliferation was measured using CellTiter-Glo® Luminescent CellViability Assay (Promega), which determines the number of viable cellsin culture based on quantitation of the ATP present, as an indicator ofmetabolically active cells. The substrate was thawed and allowed to cometo room temperature. After mixing the Cell Titer-Glo reagent and diluenttogether, 100 μL was added to each well. The plates were mixed on anorbital shaker for two minutes to induce lysis and incubated at roomtemperature for an additional ten minutes to allow the signal toequilibrate. Detection was performed using a Wallac Victor2 1420multilabel counter purchased from Perkin Elmer, Shelton, Conn. The IC₅₀calculated based on the results of this assay are provided in Table VII.

Example 4 A549 Epithelial Line Stimulated with IFNγ

A549 lung epithelial cells up-regulate ICAM-1 (CD54) surface expressionin response to a variety of different stimuli. Therefore, using ICAM-1expression as readout, compound effects on different signaling pathwayscan be assessed in the same cell type. IFNγ up-regulates ICAM-1 throughactivation of the JAK/Stat pathway. In this example, the up-regulationof ICAM-1 by IFNγ was assessed.

The A549 lung epithelial carcinoma cell line originated from theAmerican Type Culture Collection. Routine culturing was with F12K media(Mediatech Inc., Lenexa, Kans., Cat. No. 10-025-CV) with 10% fetalbovine serum, 100 I.U. penicillin and 100 ng/mL streptomycin (completeF12k media). Cells were incubated in a humidified atmosphere of 5% CO₂at 37° C. Prior to use in the assay, A549 cells were washed with PBS andtrypsinized (Mediatech Inc., Cat. No. 25-052-CI) to lift the cells. Thetrypsin cell suspension was neutralized with complete F12K media andcentrifuged to pellet the cells. The cell pellet was resuspended incomplete F12K media at a concentration of 2.0×10⁵/mL. Cells were seededat 20,000 per well, 100 μL total volume, in a flat bottom tissue cultureplate and allowed to adhere overnight.

On day two, A549 cells were pre-incubated with a 2,4-pyrimidinediaminetest compound or DMSO (control) (Sigma-Aldrich, St. Louis, Mo., CatalogNo. D2650) for 1 hour. The cells were then stimulated with IFNγ (75ng/mL) (Peprotech Inc., Rocky Hill, N.J., Cat. No. 300-02) and allowedto incubate for 24 hours. The final test compound dose range was 30 μMto 14 nM in 200 μL F12K media containing 5% FBS, 0.3% DMSO.

On day three, the cell media was removed and the cells were washed with200 μL PBS (phosphate buffered saline). Each well was trypsinized todissociate the cells, then neutralized by addition of 200 μL completeF12K media. Cells were pelleted and stained with an APC conjugated mouseanti-human ICAM-1 (CD54) (BD Pharmingen, San Diego, Calif., Catalog#559771) antibody for 20 minutes at 4° C. Cells were washed with icecold FACS buffer (PBS+2% FBS) and surface ICAM-1 expression was analyzedby flow cytometry. Detection was performed using a BD LSR I System FlowCytometer, purchased from BD Biosciences of San Jose, Calif. Events weregated for live scatter and the geometric mean was calculated(Becton-Dickinson CellQuest software version 3.3, Franklin Lakes, N.J.).Geometric means were plotted against the compound concentration togenerate a dose response curve. The IC₅₀ calculated based on the resultsof this assay are provided in Table VII.

Example 5 U937 IFNγ ICAM1 FACS Assay

Human U937 monocytic cells up-regulate ICAM-1 (CD54) surface expressionin response to a variety of different stimuli. Therefore, using ICAM-1expression as readout, compound effects on different signaling pathwayscan be assessed in the same cell type. IFNγ up-regulates ICAM-1 throughactivation of the JAK/Stat pathway. In this example, the up-regulationof ICAM-1 by IFNγ was assessed.

The U937 human monocytic cell line was obtained from ATCC of RockvilleMd., catalog number CRL-1593.2, and cultured in RPM1-1640 mediumcontaining 10% (v/v) FCS. U937 cells were grown in 10% RPMI. The cellswere then plated at a concentration of 100,000 cells per 160 μL in 96well flat bottom plates. The test compounds were then diluted asfollows: 10 mM test compound was diluted 1:5 in DMSO (3 μL 10 mM testcompound in 12 μL DMSO), followed by a 1:3 serial dilution of testcompound in DMSO (6 μL test compound serially diluted into 12 μL DMSO togive 3-fold dilutions). Then 4 μL of test compound was transferred to 76μL of 10% RPMI resulting in a 10× solution (100 μM test compound, 5%DMSO). For control wells, 4 μL of DMSO was diluted into 76 μL 10% RPMI.

The assay was performed in duplicate with 8 points (8 3-fold dilutionconcentrations from 10 μl) and with 4 wells of DMSO only (control wells)under stimulated conditions and 4 wells of DMSO only under unstimulatedconditions.

The diluted compound plate was mixed 2× using a multimek (BeckmanCoulter of Brea, Calif.) and then 20 μL of the diluted compounds wastransferred to the 96 well plate containing 160 μL of cells, which werethen mixed again twice at low speeds. The cells and compounds were thenpre-incubated for 30 minutes at 37° C. with 5% CO₂.

The 10× stimulation mix was made by preparing a 100 ng/mL solution ofhuman IFNγ in 10% RPMI. The cells and compound were then stimulated with20 μL of IFNγ stimulation mix to give a final concentration of 10 ng/mLIFNγ, 10 μM test compound, and 0.5% DMSO. The cells were kept underconditions for stimulation for 18-24 hours at 37° C. with 5% CO₂.

The cells were transferred to a 96 well round bottom plate for stainingand then kept on ice for the duration of the staining procedure. Cellswere spun down at 1000 rpm for 5 minutes at 4° C., following which thesupernatant was removed. Following removal of the supernatant, 1 μL APCconjugated mouse anti-human ICAM-1 antibody was added per 100 μL FACSbuffer. The cells were then incubated on ice in the dark for 30 minutes.Following incubation, 150 μL of FACS buffer was added and the cells werecentrifuged at 1000 rpm for 5 minutes at 4° C., following which thesupernatant was removed. After removal of the supernatant, 200 μL ofFACS buffer was added and the cells were resuspended. After suspension,the cells were centrifuged at 1000 rpm for 5 min at 4° C. Supernatantwas then removed prior to resuspension of the cells in 150 μL FACSbuffer.

Detection was performed using a BD LSR I System Flow Cytometer,purchased from BD Biosciences of San Jose, Calif. The live cells weregated for live scatter and the geometric mean of ICAM-APC was measured(Becton-Dickinson CellQuest software version 3.3, Franklin Lakes, N.J.).Both % live cells and ICAM-1 expression was analyzed. The assays for thetest compounds were carried out in parallel with a control compound ofknown activity. The EC₅₀ for the control compound is typically 40-100nM. The IC₅₀ calculated based on the results of this assay are providedin Table VII.

TABLE VII Compound # Example 2 Example 3 Example 4 Example 5 III-20.0274 0.0166 0.1635 I-18 0.7081 I-17 0.5434 I-11 0.3024 1.4512 I-7 0.1466 2.5529 I-21 2.5496 5011 I-16 0.4488 0.7889 I-6  0.1322 I-191.1218 1.9691 IV-5 3.0373 IV-2 0.1697 0.8811 3.5009 I-3  0.0931 0.78188888 I-14 0.3535 IV-3 0.2138 1.9754 I-3  0.1223 0.5795 8888 I-5  0.12940.4642 9999 0.9577 I-13 0.3311 I-1  0.0489 0.093 3.0728 0.554 IV-40.5416 I-20 1.1358 IV-1 0.1334 0.4819 18.58 I-10 0.2852 0.4235 0.4687I-12 0.3137 1.3814 I-15 0.3777 I-9  0.2243 1.3751 I-8  0.147 0.22893.8863 0.3474 I-2  0.0703 0.0796 1.7384 0.1334 V-4 0.7938 1.7205 II-10.0452 0.026 6.2315 0.0713 II-2 0.2018 0.3169 0.9908 II-3 0.3224 II-40.1356 0.4226 III-1 0.1289 0.2786 1.0796 III-3 0.0729 0.269 8888 V-112.4027 9999 V-2 14.8051 24.2124 V-3 12.883 9999 III-4 0.1011 0.12910.4620 VI-1 0.31187 VI-2 0.2792 1.0221 2.5802 V-5 0.39055

We claim:
 1. A compound of formula I:

or pharmaceutically acceptable salt thereof, wherein: ring A is heteroaryl; p is 0, 1, 2 or 3 when ring A is monocyclic or p is 0, 1, 2, 3, 4, or 5 when ring A is bi- or tricyclic; q is 0, 1, 2 or 3; X is selected from the group consisting of alkyl, substituted alkyl, hydroxy, alkoxy, substituted alkoxy, amino, substituted amino, carboxyl, carboxyl ester, cyano, halo, nitro, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkynyl, substituted cycloalkynyl; Y is selected from the group consisting of hydrogen, alk¹-SO₂N(R⁴)R⁵ and alk¹-N(R⁴)SO₂R⁵; W is selected from the group consisting of alk²-SO₂N(R⁶)R⁷ and alk²-N(R⁶)SO₂R⁷; alk¹ and alk² are each independently a bond, straight or branched chain C₁₋₆ alkylene group, cycloalkylene or substituted cycloalkylene wherein: if W is alk²-SO₂N(R⁶)R⁷ and alk² is a bond, then Y is alk¹-N(R⁴)SO₂R⁵ and alk¹ is a bond; R¹ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl and substituted cycloalkyl; each R² independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl, alkynyloxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro, halo and oxo; wherein if R² is oxo, then the oxo substituent is attached to a nonaromatic portion of ring A; or R⁴ and one of R² together with the intervening atoms bound thereto form a heterocyclic or a substituted heterocyclic fused to ring A; or R⁵ and one of R² together with the intervening atoms bound thereto form a heterocyclic or a substituted heterocyclic fused to ring A; Z¹, Z², and Z³ are carbon; and each R³ independently is selected from the group consisting of alkyl, substituted alkyl, alkoxy, substituted alkoxy, alkynyl, alkynyloxy, amino, substituted amino, aryl, substituted aryl, aryloxy, substituted aryloxy, cyano, cycloalkyl, substituted cycloalkyl, cycloalkoxy, substituted cycloalkoxy, heteroaryl, substituted heteroaryl, heteroaryloxy, substituted heteroaryloxy, heterocyclic, substituted heterocyclic, heterocyclyloxy, substituted heterocyclyloxy, aminoacyl, aminoacyloxy, carboxyl, carboxyl ester, carbonate ester, nitro, halo, and aminosulfonyl; or R⁶ and one of R³, together with the intervening atoms bound thereto, form a heterocyclic or a substituted heterocyclic fused to the ring containing Z¹, Z² and Z³; or R⁷ and one of R³, together with the intervening atoms bound thereto, form a heterocyclic or a substituted heterocyclic fused to the ring containing Z¹, Z² and Z³; or R⁴ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a counterion selected from the group consisting of K⁺, Na⁺, Li⁺ and ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen of —SO₂N(R⁴)R⁵ or —N(R⁴)SO₂R⁵ is N⁻; or R⁴ and R⁵ together with the intervening atom or atoms bound thereto form a heterocyclic or substituted heterocyclic group; or R⁵ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, and acyl; or R⁴ and R⁵ together with the intervening atom or atoms bound thereto form a heterocyclic or a substituted heterocyclic group; R⁶ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, carboxyl, carboxyl ester, aryl, substituted aryl, heteroaryl, substituted heteroaryl, acyl and M⁺, wherein M⁺ is a counterion selected from the group consisting of K⁺, Na⁺, Li⁺ or ⁺N(R⁸)₄, wherein R⁸ is hydrogen or alkyl, and the nitrogen of —SO₂N(R⁶)R⁷ or —N(R⁶)SO₂R⁷ is N⁻; or R⁶ and R⁷ together with the intervening atom or atoms bound thereto, form a heterocyclic or a substituted heterocyclic group; or if W is alk²-SO₂N(R⁶)R⁷, then R⁶ and R⁷ together with the nitrogen atom bound thereto optionally form —N═C(OR⁹)₂ wherein each R⁹ independently is an alkyl group; and R⁷ is selected from the group consisting of hydrogen, alkyl, substituted alkyl, amino, cycloalkyl, substituted cycloalkyl, heterocyclic, substituted heterocyclic, aryl, substituted aryl, heteroaryl, substituted heteroaryl, carboxyl, carboxyl ester, and acyl; provided that when X is hydrogen, ring A is not benzimidazolyl or indazolyl.
 2. The compound of claim 1, wherein the compound is represented by formula II:


3. The compound of claim 2 wherein the compound is represented by formula III


4. The compound of claim 3, wherein X is fluoro, alk² is —CH₂— and each of R⁶ and R⁷ independently is hydrogen or alkyl.
 5. The compound of claim 4, wherein ring A is a bicyclic heteroaryl.
 6. The compound of claim 5, wherein:

wherein R is hydrogen or methyl.
 7. The compound of claim 5, wherein each R² independently is selected from the group consisting of alkyl, substituted alkyl, aminoacyl, alkynyl, and oxo; wherein if R² is oxo, then the oxo substituent is attached to a nonaromatic portion of ring A.
 8. The compound of claim 4, wherein Y is -alk¹-N(R⁴)SO₂R⁵.
 9. The compound of claim 8, wherein alk¹ is —CH₂— and each of R⁴ and R⁵ independently is hydrogen or alkyl.
 10. The compound of claim 4, wherein Y is -alk¹-SO₂N(R⁴)R⁵.
 11. The compound of claim 10, wherein alk¹ is a bond and each of R⁴ and R⁵ independently is hydrogen or alkyl.
 12. The compound of claim 10, wherein alk¹ is —CH₂— and each of R⁴ and R⁵ independently is selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, heterocyclic and substituted heterocyclic.
 13. The compound of claim 2 wherein the compound is represented by formula IV:


14. The compound of claim 13, wherein Y is hydrogen or alk¹-N(R⁴)SO₂R⁵ and X is halo, methyl or trifluoromethyl.
 15. The compound of claim 14, wherein X is fluoro.
 16. The compound of claim 14, wherein each of alk¹ and alk² is —CH₂— or —CH₂CH₂— and each of R⁴, R⁵, R⁶ and R⁷ independently is selected from the group consisting of hydrogen, cycloalkyl, and heteroaryl.
 17. The compound of claim 14, wherein alk² is —CH₂— and R⁶ and one of R³ together with the intervening atoms bound thereto, form a heterocyclic or substituted heterocyclic.
 18. The compound of claim 17, wherein the compound is represented by formula V:


19. The compound of claim 14, wherein ring A is

and Y is hydrogen.
 20. The compound of claim 1 selected from the group consisting of: IV-5 N2-(3-Aminosulfonylmethylenephenyl)-5-fluoro-N-4-[2-(2-N-morpholinoethylaminoacarbonyl)benzofuran-5-yl]-2,4-pyrimidinediamine; IV-2 N2-[3-(Aminosulfonylmethylene)phenyl]-N-4-[2,2-dimethyl-3-oxo-4-methyl-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine; IV-3 N2-(3-Aminosulfonylmethylphenyl)-5-fluoro-N-4-[1-(propyn-3-yl)indol-5-yl]-2,4-pyrimidinediamine; IV-4 N2-[3-(Aminosulfonylmethylene)phenyl]-N4-(3-cyanomethylene-1H-indol-5-yl)-5-fluoro-2,4-pyrimidinediamine; IV-1 N2-[3-(Aminosulfonylmethylene)phenyl]-N-4-[2,2-dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-5-fluoro-2,4-pyrimidinediamine; III-3 N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(2,2-dimethyl-3-oxo-4H-5-pyrid[1,4]oxazin-6-yl)-5-fluoro-2,4-pyrimidinediamine; V-1 N2-(4-Aminosulfonyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine; V-2 N2-(3-Aminosulfonyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine; V-3 N2-(3-Aminosulfonyl-4-methyl)phenyl-5-fluoro-N4-(2,2-dioxo-5-fluoro-1,3-dihydrobenzo[c]isothiazol-6-yl)-2,4-pyrimidinediamine; V-4 N4-[2,2-Dimethyl-3-oxo-4H-pyrid[1,4]oxazin-7-yl]-N2-[3,3-dioxo-1H-benzo[e][1,3,4]oxathiazin-7-yl]-5-fluoro-2,4-pyrimidinediamine; V-5 N2-(3-Benzyl-cyclopropanesulfonamide)-N4-(3,4-tetrahydropyrid[1]pyranon-6-yl)-5-methyl-2,4-pyrimidinediamine; III-4 N2-(2-Aminosulfonyl-1,2,3,4-tetrahydroisoquinolin-7-yl)-N4-(4-(prop-2-ynyloxy)phenyl)-5-fluoro-2,4-pyrimidinediamine; and N2-(3-Benzyl-cyclopropanesulfonamide)-N4-(3,4-dihydroquinolin-1H-6-yl)-5-methyl-2,4-pyrimidinediamine.
 21. A pharmaceutical formulation comprising a compound according to claim
 1. 22. The compound of claim 1, wherein ring A is 